Cytosolic GDH1 degradation restricts protein synthesis to sustain tumor cell survival following amino acid deprivation

Correction to: The EMBO Journal (2021) 40: e107480. DOI 10.15252/embj.2020107480 ¦ Published online 6 July 2021The authorship of this research paper is herewith corrected to indicate that Jialiang Shao, Tiezhu Shi, Hua Yu, and Yufeng Ding are all equal co‐first authors.     

Molecular basis of cross‐species ACE2 interactions with SARS‐CoV‐2‐like viruses of pangolin origin

Correction to: The EMBO Journal (2021) 40: e107786. DOI 10.15252/embj.2021107786 | Published online 8 June 2021The authors would like to add three references to the paper: Starr et al and Zahradník et al also reported that the Q498H or Q498R mutation has enhanced binding affinity to ACE2; and Liu et al reported on the binding of bat coronavirus to ACE2.Starr et al and Zahradník et al have now been cited in the Discussion section, and the following sentence has been corrected from:“According to our data, the SARS‐CoV‐2 RBD with Q498H increases the binding strength to hACE2 by 5‐fold, suggesting the Q498H mutant is more ready to interact with human receptor than the wildtype and highlighting the necessity for more strict control of virus and virus‐infected animals”.to“Here, according to our data and two recently published papers, the SARS‐CoV‐2 RBD with Q498H or Q498R increases the binding strength to hACE2 (Starr et al, 2020; Zahradník et al, 2021), suggesting the mutant with Q498H or Q498R is more ready to interact with human receptor than the wild type and highlighting the necessity for more strict control of virus and virus‐infected animals”.The Liu et al citation has been added to the following sentence:“In another paper published by our group recently, RaTG13 RBD was found to bind to hACE2 with much lower binding affinity than SARS‐CoV‐2 though RaTG13 displays the highest whole‐genome sequence identity (96.2%) with the SARS‐CoV‐2 (Liu et al, 2021)”.Additionally, the authors have added the GISAID accession IDs to the sequence names of the SARS‐CoV‐2 in two human samples (Discussion section). To make identification unambiguous, the sequence names have been updated from “SA‐lsf‐27 and SA‐lsf‐37” to “GISAID accession ID: EPI_ISL_672581 and EPI_ISL_672589”.Lastly, the authors declare in the Materials and Methods section that all experiments employed SARS‐CoV‐2 pseudovirus in cultured cells. These experiments were performed in a BSL‐2‐level laboratory and approved by Science and Technology Conditions Platform Office, Institute of Microbiology, Chinese Academy of Sciences.These changes are herewith incorporated into the paper.     

Inactive variants of death receptor p75NTR reduce Alzheimer’s neuropathology by interfering with APP internalization

A prevalent model of Alzheimer’s disease (AD) pathogenesis postulates the generation of neurotoxic fragments derived from the amyloid precursor protein (APP) after its internalization to endocytic compartments. The molecular pathways that regulate APP internalization and intracellular trafficking in neurons are incompletely understood. Here, we report that 5xFAD mice, an animal model of AD, expressing signaling‐deficient variants of the p75 neurotrophin receptor (p75^NTR) show greater neuroprotection from AD neuropathology than animals lacking this receptor. p75^NTR knock‐in mice lacking the death domain or transmembrane Cys²⁵⁹ showed lower levels of Aβ species, amyloid plaque burden, gliosis, mitochondrial stress, and neurite dystrophy than global knock‐outs. Strikingly, long‐term synaptic plasticity and memory, which are completely disrupted in 5xFAD mice, were fully recovered in the knock‐in mice. Mechanistically, we found that p75^NTR interacts with APP at the plasma membrane and regulates its internalization and intracellular trafficking in hippocampal neurons. Inactive p75^NTR variants internalized considerably slower than wild‐type p75^NTR and showed increased association with the recycling pathway, thereby reducing APP internalization and co‐localization with BACE1, the critical protease for generation of neurotoxic APP fragments, favoring non‐amyloidogenic APP cleavage. These results reveal a novel pathway that directly and specifically regulates APP internalization, amyloidogenic processing, and disease progression, and suggest that inhibitors targeting the p75^NTR transmembrane domain may be an effective therapeutic strategy in AD.     

Caspase‐12 and endoplasmic reticulum stress mediate neurotoxicity of pathological prion protein

Correction to: The EMBO Journal (2003) 22: 5435–5445. DOI 10.1093/emboj/cdg537 ¦ Published online 15 October 2003 Figure 7A. Original.Source data are available online for this figure. Figure 7A. Corrected. Source data are available online for this figure. The journal was informed of potential image aberrations in Fig 7A. The authors claim that the loading control in the originally published figure corresponded to a replicate experiment as many Western blots were run in parallel with the same samples to measure levels of ER stress markers. The control panel in Fig 7A is herewith retracted and replaced with the author‐supplied loading control of the experiment shown in Fig 7A.The journal noted that Fig 3 and Appendix Figure 3 were duplicated and that the legend to Appendix Figure 3 did not match the displayed figure. The authors recovered the quantification data for Appendix Figure 3, but not the scanned blots. The authors state that they no longer have access to the laboratory books or primary data and that they cannot definitively say which image was analysed. The authors withdraw Appendix Figure 3.The authors also acknowledge that there are undeclared splice sites in Fig 3, but that they could not locate the source data.The source data for Fig 7A are available with this corrigendum notice.The authors apologize for these errors and agree with this corrigendum; no response could be obtained from MR‐C.     

BH3‐only proteins are part of a regulatory network that control the sustained signalling of the unfolded protein response sensor IRE1α

Correction to: The EMBO Journal (2012) 31: 2322–2335. DOI 10.1038/emboj.2012.84 ¦ Published online 17 April 2012 Figure 4A. Original.Source data are available online for this figure. Figure 4A. Corrected. Source data are available online for this figure. The journal was alerted to the claim that the IRE input panels are identical in Figure 1G. Since the IRE input panels show a high degree of similarity, the source data for both panels are published with this notice for the avoidance of doubt.The HSP90 blot looks very similar in Fig 3F and Fig S4A. The authors confirmed that they had stripped and re‐probed the original HSP90 blot in Fig 3F and Fig S4A. Specifically, the membrane was probed with antibodies to IRE1, and HSP90, and then re‐probed with anti‐PERK antibodies. For that reason, HSP90 was presented in both figures because it is the same experiment. In the source data published with this correction, the authors have marked the original data with contrast boxes and arrows to indicate which blots were presented in the figure. The legends have been updated to state that a control originating from one blot is displayed in both figures.The authors acknowledge that they had removed one set of experimental conditions with wild‐type parental DKO cells when preparing Fig 4A and state that this does not change the conclusions of the figure. The figure is herewith updated with a demarcating line and source data for the full experiment is published with this notice.All authors agree with this corrigendum. The authors apologize for any confusion caused by these errors.     

Posttranscriptional regulation of colonic epithelial repair by RNA binding protein IMP1/IGF2BP1

Correction to: EMBO Reports (2019) 20: e47074. DOI 10.15252/embr.201847074 | Published online 6 May 2019The authors noticed that the control and disease labels had been inverted in their data analysis resulting in publication of incorrect data in Figure 1C. The corrected figure is displayed below. This change affects the conclusions as detailed below. The authors apologize for this error and any confusion it may have caused.In the legend of 1C, change from, “Differential gene expression analysis of pediatric ileal CD patient samples (n = 180) shows increased (> 4‐fold) IMP1 expression as compared to non‐inflammatory bowel disease (IBD) pediatric samples (n = 43)”.Open in a separate windowFigure 1CCorrected Open in a separate windowFigure 1COriginal To, "Differential gene expression analysis of pediatric ileal CD patient samples (n = 180) shows decreased (> 4‐fold) IMP1 expression as compared to non‐inflammatory bowel disease (IBD) pediatric samples (n = 43)”.In abstract, change from, “Here, we report increased IMP1 expression in patients with Crohn''s disease and ulcerative colitis”.To, “Here, we report increased IMP1 expression in adult patients with Crohn''s disease and ulcerative colitis”.In results, change from, “Consistent with these findings, analysis of published the Pediatric RISK Stratification Study (RISK) cohort of RNA‐sequencing data 38 from pediatric patients with Crohn''s disease (CD) patients revealed that IMP1 is upregulated significantly compared to control patients and that this effect is specific to IMP1 (i.e., other distinct isoforms, IMP2 and IMP3, are not changed; Fig 1C)”.To, “Contrary to our findings in colon tissue from adults, analysis of published RNA‐sequencing data from the Pediatric RISK Stratification Study (RISK) cohort of ileal tissue from children with Crohn’s disease (CD) 38 revealed that IMP1 is downregulated significantly compared to control patients in the RISK cohort and that this effect is specific to IMP1 (i.e., other distinct isoforms, IMP2 and IMP3, are not changed; Fig 1C)”.In discussion, change from, “Indeed, we report that IMP1 is upregulated in patients with Crohn''s disease and ulcerative colitis and that mice with Imp1 loss exhibit enhanced repair following DSS‐mediated damage”.To “Indeed, we report that IMP1 is upregulated in adult patients with Crohn''s disease and ulcerative colitis and that mice with Imp1 loss exhibit enhanced repair following DSS‐mediated damage”.     

Repetitive transcranial magnetic stimulation for smoking cessation: a pivotal multicenter double‐blind randomized controlled trial

Repetitive transcranial magnetic stimulation (rTMS) is a non‐invasive brain stimulation method increasingly used to treat psychiatric disorders, primarily depression. Initial studies suggest that rTMS may help to treat addictions, but evaluation in multicenter randomized controlled trials (RCTs) is needed. We conducted a multicenter double‐blind RCT in 262 chronic smokers meeting DSM‐5 criteria for tobacco use disorder, who had made at least one prior failed attempt to quit, with 68% having made at least three failed attempts. They received three weeks of daily bilat­eral active or sham rTMS to the lateral prefrontal and insular cortices, followed by once weekly rTMS for three weeks. Each rTMS session was administered following a cue‐induced craving procedure, and participants were monitored for a total of six weeks. Those in abstinence were monitored for additional 12 weeks. The primary outcome measure was the four‐week continuous quit rate (CQR) until Week 18 in the intent‐to‐treat efficacy set, as determined by daily smoking diaries and verified by urine cotinine measures. The trial was registered at ClinicalTrials.gov ({"type":"clinical-trial","attrs":{"text":"NCT02126124","term_id":"NCT02126124"}}NCT02126124). In the intent‐to‐treat analysis set (N=234), the CQR until Week 18 was 19.4% following active and 8.7% following sham rTMS (X²=5.655, p=0.017). Among completers (N=169), the CQR until Week 18 was 28.0% and 11.7%, respectively (X²=7.219, p=0.007). The reduction in cigarette consumption and craving was significantly greater in the active than the sham group as early as two weeks into treatment. This study establishes a safe treatment protocol that promotes smoking cessation by stimulating relevant brain circuits. It represents the first large multicenter RCT of brain stimulation in addiction medicine, and has led to the first clearance by the US Food and Drug Administration for rTMS as an aid in smok­ing cessation for adults.     

LINGO-1 Protein Interacts with the p75 Neurotrophin Receptor in Intracellular Membrane Compartments

Axon outgrowth inhibition in response to trauma is thought to be mediated via the binding of myelin-associated inhibitory factors (e.g. Nogo-66, myelin-associated glycoprotein, oligodendrocyte myelin glycoprotein, and myelin basic protein) to a putative tripartite LINGO-1·p75^NTR·Nogo-66 receptor (NgR) complex at the cell surface. We found that endogenous LINGO-1 expression in neurons in the cortex and cerebellum is intracellular. Mutation or truncation of the highly conserved LINGO-1 C terminus altered this intracellular localization, causing poor intracellular retention and increased plasma membrane expression. p75^NTR associated predominantly with natively expressed LINGO-1 containing immature N-glycans, characteristic of protein that has not completed trans-Golgi-mediated processing, whereas mutant forms of LINGO-1 with enhanced plasma membrane expression did not associate with p75^NTR. Co-immunoprecipitation experiments demonstrated that LINGO-1 and NgR competed for binding to p75^NTR in a manner that is difficult to reconcile with the existence of a LINGO-1·p75^NTR·NgR ternary complex. These findings contradict models postulating functional LINGO-1·p75^NTR·NgR complexes in the plasma membrane.     

Membrane protein biogenesis by the EMC

Recent cryo‐EM‐based models reveal how the ER membrane protein complex may accomplish insertion of protein transmembrane domains with limited hydrophobicity.

Insertion of strongly hydrophobic TMDs into the ER membrane is mediated by the Sec61 complex for co‐translational insertion and the GET complex for post‐translational insertion of tail‐anchors (Volkmar & Christianson, 2020). By contrast, the EMC inserts TMDs of limited hydrophobicity, frequently located at the N‐ or C‐termini of proteins, and is involved in biogenesis of multi‐spanning membrane proteins (Volkmar & Christianson, 2020).The EMC is highly conserved (Wideman, 2015). In vertebrates, ten subunits have been identified (EMC1‐10), two of which, EMC8 and EMC9, are homologous and the result of a vertebrate‐specific gene duplication (Wideman, 2015). In Saccharomyces cerevisiae, EMC8 has been lost (Wideman, 2015). Only EMC3 displays clear homology to other membrane protein insertases, the Oxa1 family (Wideman, 2015; Volkmar & Christianson, 2020). This family includes YidC, which inserts TMDs into the bacterial cytoplasmic membrane, usually in cooperation with the Sec61‐homologous SecYEG channel (Volkmar & Christianson, 2020). Their association, along with the SecDF ancillary complex, forms a holo‐translocon capable of protein secretion and TMD insertion, with striking similarities to the EMC complex (Martin et al, 2019).Recent work by Pleiner et al (2020) presented a 3.4 Å cryo‐EM structure of the human EMC purified via a GFP‐tag on EMC2 and incorporated into a phospholipid nanodisc. The complex is formed by nine proteins (EMC1‐8, EMC10) (Pleiner et al, 2020). EMC8 and EMC9 are structurally similar, and their association with EMC2 is mutually exclusive (O''Donnell et al, 2020). Of the 12 TMDs, nine constitute the pseudosymmetric central ordered core, with a basket‐shaped cytosolic vestibule formed primarily by alpha‐helices of the EMC3 and EMC6 TMDs and cytosolic EMC2 (Fig 1A; Pleiner et al, 2020). The L‐shaped lumenal domain of the EMC consists mostly of beta‐sheets (Fig 1A; Pleiner et al, 2020), flanked by a conspicuous and conserved amphipathic alpha‐helix of EMC1 sealing the vestibule at the interface between the membrane and the ER lumen, together with another smaller amphipathic helix contributed by EMC3 (Fig 1A; Pleiner et al, 2020). In the ER lumen, the two 8‐bladed propellers of EMC1 contact six of the eight other subunits and stabilize the entire complex (Fig 1A; Pleiner et al, 2020). Beta‐sandwiches of EMC7 and EMC10 are anchored to the EMC1 lumenal domain (Fig 1A; Pleiner et al, 2020). In the cytosol, the tetratricopeptide repeat (TPR) spiral of EMC2 forms a cup underneath the partially hydrophilic vestibule in the membrane between the TMDs of EMC3 and EMC6, bridging the cytosolic ends of TMDs of EMC1, 3 and 5 (Fig 1A; Pleiner et al, 2020). Cytosolic EMC8 is bound to the opposite face of EMC2 (Fig 1A).Open in a separate windowFigure 1Comparison of the structures of human and yeast EMC(A) Cryo‐EM 3D map of the human (emdb‐21929) and yeast (emdb‐21587) EMC, showing front and back views with individual subunits coloured. Membrane position, obtained from the OPM database, is shown by grey discs. (B) Close‐up view of the EMC cavity formed by EMC3 and EMC6. Left, shown in a hydrophobicity surface pattern. Right, surface representation overlapped with the TMDs of EMC3 and EMC6. EMC4, flexible and with a gate function at the substrate‐binding place, is shown in pink in the yeast representation. EMC4 is not visible at the atomic EMC human structure, although is observed as a weak density at the human model, accompanied by TMs of EMC7 and EMC10 (Pleiner et al, 2020). (C) The yeast EMC following > 5 µs of CG‐MD simulation. The protein is shown as surface and coloured as per Pleiner et al (2020). The computed densities of waters and phospholipid tails and phosphates are shown as blue, yellow and lime green densities, sliced to bisect the cavity for clarity. Right, inset of the EMC cavity. Methods: CG‐MD simulations were built using PDB 6WB9 in a solvated symmetric POPC/POPE/cholesterol membrane and run in the Martini forcefield as described in Martin et al (2019). 3 µs unrestrained simulations were run, followed by 2.5 µs backbone restrained simulation for density calculation, done using VolMap in VMD (Humphrey et al, 1996).The 3.0 Å cryo‐EM structure of the yeast EMC presented by Bai and colleagues shows a very similar overall organization (Bai et al, 2020). Here, purification was via a 3xFLAG‐tag on EMC5, and the structure of the 8‐subunit complex (without EMC8/9) was visualized in detergent solution (Bai et al, 2020). The yeast complex has twelve TMDs like the human EMC, but unlike the human structure, EMC4 in yeast has three TMDs that are clearly visible (Bai et al, 2020). They are angled in the membrane pointing away from the complex at the cytosolic end (Fig 1A), and Bai et al (2020) propose that TMDs of EMC4, EMC3 and EMC6 form a substrate‐binding pocket similar to that of YidC. As in the human EMC, there are two amphipathic helices (EMC1 and EMC3) at the membrane/lumen interface (Fig 1A; Bai et al, 2020). In the ER lumen, yeast EMC1 only has one 8‐bladed beta‐propeller, to which the beta‐sandwiches of EMC7 and EMC10 are anchored (Fig 1A; Bai et al, 2020). In the cytosol, EMC2 bridges EMC3, 4 and 5, and its TPR repeats form a cup underneath the vestibule similar to human EMC2 (Fig 1A; Bai et al, 2020).The authors propose that insertion of a partially hydrophilic TMD by the yeast EMC is mechanistically similar to insertion by bacterial YidC (Bai et al, 2020). Yeast EMC is proposed to bind substrate between TMD2 of EMC3 and TMD2 of EMC4 in a pocket with polar and positively charged amino acids at either end and hydrophobic amino acids in the centre (Fig 1B; Bai et al, 2020). Much has been made of a conserved positive region within the EMC complex here, present in an equivalent position also in YidC (Kumazaki et al, 2014): It is claimed to be important for the incorporation of more‐hydrophilic TMDs and perhaps responsible for the “positive‐inside” orientation rule (von Heijne, 1992). Yeast and human EMC3 contain a specific R31 and R26 residue, respectively, conserved also in YidC and important for function of the EMC, as well as for YidC in Gram‐positive, but interestingly not Gram‐negative, bacteria (Chen et al, 2014; Pleiner et al, 2020; Bai et al, 2020). Another interesting feature, also conserved with YidC, is the flexibility of the TMDs flanking the substrate‐binding pocket, critical for EMC entry of substrates (Bai et al, 2020).In the human EMC, methionine residues in a cytosolic loop of EMC3 act as a substrate bait (Pleiner et al, 2020). Polar and charged residues within the substrate‐binding groove guide the lumenal domain across the membrane, facilitated by local membrane thinning (Pleiner et al, 2020; Fig 1B). The positive charges within the substrate‐binding site exclude signal peptides and enforce the “positive‐inside rule” (von Heijne, 1992; Pleiner et al, 2020). Flexible TMDs of EMC4, EMC7 and EMC10 forming a “lateral gate” of the substrate‐binding groove allow sampling of the bilayer by the substrate TMD (Pleiner et al, 2020). As the shortened TMDs of EMC3 and EMC6 cannot stably bind the substrate TMD, they favour its release into the bilayer (Pleiner et al, 2020). The EMC1 beta‐propeller(s) may recruit additional protein maturation factors in the ER lumen (Pleiner et al, 2020; Bai et al, 2020) or bind the Sec61 channel to allow cooperation between the two insertases (Bai et al, 2020).Arguably, the most interesting feature of the EMC complex is the location of a large interior cavity with distinctive hydrophilic character, which likely aids TMD insertion (Fig 1B). We ran a coarse‐grained molecular dynamics (CG‐MD) simulation of the yeast EMC structure, which highlights a profound perturbation of the phospholipid bilayer in the EMC interior cavity (Fig 1C). Here, a deep gorge forms in the cytoplasmic leaflet of the bilayer, allowing the cavity to become flooded with water (Fig 1C). Note the location of the lipid head groups here (lime green), which presumably define the site of amphipathic TMD insertion. The incursion of phospholipids into the centre of the EMC complex is a feature shared by the bacterial holo‐translocon (Martin et al, 2019) and perhaps by all membrane protein insertases. The shape and character of the EMC cavity presumably dictate its predisposition for less hydrophobic TMDs; it would be interesting to see whether the cavities of different insertases are similarly tailored to suit their substrates.     

Association between Obstructive Sleep Apnea and Community-Acquired Pneumonia

BackgroundWe hypothesized that obstructive sleep apnea (OSA) can predispose individuals to lower airway infections and community-acquired pneumonia (CAP) due to upper airway microaspiration. This study evaluated the association between OSA and CAP.MethodsWe performed a case-control study that included 82 patients with CAP and 41 patients with other infections (control group). The controls were matched according to age, sex and body mass index (BMI). A respiratory polygraph (RP) was performed upon admission for patients in both groups. The severity of pneumonia was assessed according to the Pneumonia Severity Index (PSI). The associations between CAP and the Epworth Sleepiness Scale (ESS), OSA, OSA severity and other sleep-related variables were evaluated using logistic regression models. The associations between OSA, OSA severity with CAP severity were evaluated with linear regression models and non-parametric tests.FindingsNo significant differences were found between CAP and control patients regarding anthropometric variables, toxic habits and risk factors for CAP. Patients with OSA, defined as individuals with an Apnea-Hypopnea Index (AHI) ≥10, showed an increased risk of CAP (OR = 2·86, 95%CI 1·29–6·44, p = 0·01). Patients with severe OSA (AHI≥30) also had a higher risk of CAP (OR = 3·18, 95%CI 1·11–11·56, p = 0·047). In addition, OSA severity, defined according to the AHI quartile, was also significantly associated with CAP (p = 0·007). Furthermore, OSA was significantly associated with CAP severity (p = 0·0002), and OSA severity was also associated with CAP severity (p = 0·0006).ConclusionsOSA and OSA severity are associated with CAP when compared to patients admitted to the hospital for non-respiratory infections. In addition, OSA and OSA severity are associated with CAP severity. These results support the potential role of OSA in the pathogenesis of CAP and could have clinical implications. This link between OSA and infection risk should be explored to investigate the relationships among gastroesophageal reflux, silent aspiration, laryngeal sensory dysfunction and CAP.

Trial Registration

ClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01071421","term_id":"NCT01071421"}}NCT01071421     

Transvenous vagus nerve stimulation does not modulate the innate immune response during experimental human endotoxemia: a randomized controlled study

IntroductionVagus nerve stimulation (VNS) exerts beneficial anti-inflammatory effects in various animal models of inflammation, including collagen-induced arthritis, and is implicated in representing a novel therapy for rheumatoid arthritis. However, evidence of anti-inflammatory effects of VNS in humans is very scarce. Transvenous VNS (tVNS) is a newly developed and less invasive method to stimulate the vagus nerve. In the present study, we determined whether tVNS is a feasible and safe procedure and investigated its putative anti-inflammatory effects during experimental human endotoxemia.MethodsWe performed a randomized double-blind sham-controlled study in healthy male volunteers. A stimulation catheter was inserted in the left internal jugular vein at spinal level C5–C7, adjacent to the vagus nerve. In the tVNS group (n = 10), stimulation was continuously performed for 30 minutes (0–10 V, 1 ms, 20 Hz), starting 10 minutes before intravenous administration of 2 ng kg⁻¹Escherichia coli lipopolysaccharide (LPS). Sham-instrumented subjects (n = 10) received no electrical stimulation.ResultsNo serious adverse events occurred throughout the study. In the tVNS group, stimulation of the vagus nerve was achieved as indicated by laryngeal vibration. Endotoxemia resulted in fever, flu-like symptoms, and hemodynamic changes that were unaffected by tVNS. Furthermore, plasma levels of inflammatory cytokines increased sharply during endotoxemia, but responses were similar between groups. Finally, cytokine production by leukocytes stimulated with LPS ex vivo, as well as neutrophil phagocytosis capacity, were not influenced by tVNS.ConclusionstVNS is feasible and safe, but does not modulate the innate immune response in humans in vivo during experimental human endotoxemia.

Trial registration

Clinicaltrials.gov {"type":"clinical-trial","attrs":{"text":"NCT01944228","term_id":"NCT01944228"}}NCT01944228. Registered 12 September 2013.     

Xanthomonas hortorum – beyond gardens: Current taxonomy,genomics, and virulence repertoires

TaxonomyBacteria; Phylum Proteobacteria; Class Gammaproteobacteria; Order Lysobacterales (earlier synonym of Xanthomonadales); Family Lysobacteraceae (earlier synonym of Xanthomonadaceae); Genus Xanthomonas; Species X. hortorum; Pathovars: pv. carotae, pv. vitians, pv. hederae, pv. pelargonii, pv. taraxaci, pv. cynarae, and pv. gardneri.Host range Xanthomonas hortorum affects agricultural crops, and horticultural and wild plants. Tomato, carrot, artichoke, lettuce, pelargonium, ivy, and dandelion were originally described as the main natural hosts of the seven separate pathovars. Artificial inoculation experiments also revealed other hosts. The natural and experimental host ranges are expected to be broader than initially assumed. Additionally, several strains, yet to be assigned to a pathovar within X. hortorum, cause diseases on several other plant species such as peony, sweet wormwood, lavender, and oak‐leaf hydrangea.Epidemiology and control X. hortorum pathovars are mainly disseminated by infected seeds (e.g., X. hortorum pvs carotae and vitians) or cuttings (e.g., X. hortorum pv. pelargonii) and can be further dispersed by wind and rain, or mechanically transferred during planting and cultivation. Global trade of plants, seeds, and other propagating material constitutes a major pathway for their introduction and spread into new geographical areas. The propagules of some pathovars (e.g., X. horturum pv. pelargonii) are spread by insect vectors, while those of others can survive in crop residues and soils, and overwinter until the following growing season (e.g., X. hortorum pvs vitians and carotae). Control measures against X. hortorum pathovars are varied and include exclusion strategies (i.e., by using certification programmes and quarantine regulations) to multiple agricultural practices such as the application of phytosanitary products. Copper‐based compounds against X. hortorum are used, but the emergence of copper‐tolerant strains represents a major threat for their effective management. With the current lack of efficient chemical or biological disease management strategies, host resistance appears promising, but is not without challenges. The intrastrain genetic variability within the same pathovar poses a challenge for breeding cultivars with durable resistance.Useful websites https://gd.eppo.int/taxon/XANTGA, https://gd.eppo.int/taxon/XANTCR, https://gd.eppo.int/taxon/XANTPE, https://www.euroxanth.eu, http://www.xanthomonas.org, http://www.xanthomonas.org/dokuwiki     

Soluble β-amyloid Precursor Protein Alpha Binds to p75 Neurotrophin Receptor to Promote Neurite Outgrowth

Background

The cleavage of β-amyloid precursor protein (APP) generates multiple proteins: Soluble β-amyloid Precursor Protein Alpha (sAPPα), sAPPβ, and amyloid β (Aβ). Previous studies have shown that sAPPα and sAPPβ possess neurotrophic properties, whereas Aβ is neurotoxic. However, the underlying mechanism of the opposing effects of APP fragments remains poorly understood. In this study, we have investigated the mechanism of sAPPα-mediated neurotrophic effects. sAPPα and sAPPβ interact with p75 neurotrophin receptor (p75^NTR), and sAPPα promotes neurite outgrowth.

Methods and Findings

First, we investigated whether APP fragments interact with p75^NTR, because full-length APP and Aβ have been shown to interact with p75^NTR in vitro. Both sAPPα and sAPPβ were co-immunoprecipitated with p75^NTR and co-localized with p75^NTR on COS-7 cells. The binding affinity of sAPPα and sAPPβ for p75^NTR was confirmed by enzyme-linked immunosorbent assay (ELISA). Next, we investigated the effect of sAPPα on neurite outgrowth in mouse cortical neurons. Neurite outgrowth was promoted by sAPPα, but sAPPα was uneffective in a knockdown of p75^NTR.

Conclusion

We conclude that p75^NTR is the receptor for sAPPα to mediate neurotrophic effects.     

Age‐related changes in hippocampal‐dependent synaptic plasticity and memory mediated by p75 neurotrophin receptor

The plasticity mechanisms in the nervous system that are important for learning and memory are greatly impacted during aging. Notably, hippocampal‐dependent long‐term plasticity and its associative plasticity, such as synaptic tagging and capture (STC), show considerable age‐related decline. The p75 neurotrophin receptor (p75^NTR) is a negative regulator of structural and functional plasticity in the brain and thus represents a potential candidate to mediate age‐related alterations. However, the mechanisms by which p75^NTR affects synaptic plasticity of aged neuronal networks and ultimately contribute to deficits in cognitive function have not been well characterized. Here, we report that mutant mice lacking the p75^NTR were resistant to age‐associated changes in long‐term plasticity, associative plasticity, and associative memory. Our study shows that p75^NTR is responsible for age‐dependent disruption of hippocampal homeostatic plasticity by modulating several signaling pathways, including BDNF, MAPK, Arc, and RhoA‐ROCK2‐LIMK1‐cofilin. p75^NTR may thus represent an important therapeutic target for limiting the age‐related memory and cognitive function deficits.     

Ascochyta rabiei: A threat to global chickpea production

The necrotrophic fungus Ascochyta rabiei causes Ascochyta blight (AB) disease in chickpea. A. rabiei infects all aerial parts of the plant, which results in severe yield loss. At present, AB disease occurs in most chickpea‐growing countries. Globally increased incidences of A. rabiei infection and the emergence of new aggressive isolates directed the interest of researchers toward understanding the evolution of pathogenic determinants in this fungus. In this review, we summarize the molecular and genetic studies of the pathogen along with approaches that are helping in combating the disease. Possible areas of future research are also suggested.Taxonomykingdom Mycota, phylum Ascomycota, class Dothideomycetes, subclass Coelomycetes, order Pleosporales, family Didymellaceae, genus Ascochyta, species rabiei. Primary host A. rabiei survives primarily on Cicer species.Disease symptoms A. rabiei infects aboveground parts of the plant including leaves, petioles, stems, pods, and seeds. The disease symptoms first appear as watersoaked lesions on the leaves and stems, which turn brown or dark brown. Early symptoms include small circular necrotic lesions visible on the leaves and oval brown lesions on the stem. At later stages of infection, the lesions may girdle the stem and the region above the girdle falls off. The disease severity increases at the reproductive stage and rounded lesions with concentric rings, due to asexual structures called pycnidia, appear on leaves, stems, and pods. The infected pod becomes blighted and often results in shrivelled and infected seeds.Disease management strategiesCrop failures may be avoided by judicious practices of integrated disease management based on the use of resistant or tolerant cultivars and growing chickpea in areas where conditions are least favourable for AB disease development. Use of healthy seeds free of A. rabiei, seed treatments with fungicides, and proper destruction of diseased stubbles can also reduce the fungal inoculum load. Crop rotation with nonhost crops is critical for controlling the disease. Planting moderately resistant cultivars and prudent application of fungicides is also a way to combat AB disease. However, the scarcity of AB‐resistant accessions and the continuous evolution of the pathogen challenges the disease management process.Useful websites https://www.ndsu.edu/pubweb/pulse‐info/resourcespdf/Ascochyta%20blight%20of%20chickpea.pdf https://saskpulse.com/files/newsletters/180531_ascochyta_in_chickpeas‐compressed.pdf http://www.pulseaus.com.au/growing‐pulses/bmp/chickpea/ascochyta‐blight http://agriculture.vic.gov.au/agriculture/pests‐diseases‐and‐weeds/plant‐diseases/grains‐pulses‐and‐cereals/ascochyta‐blight‐of‐chickpea http://www.croppro.com.au/crop_disease_manual/ch05s02.php https://www.northernpulse.com/uploads/resources/722/handout‐chickpeaascochyta‐nov13‐2011.pdf http://oar.icrisat.org/184/1/24_2010_IB_no_82_Host_Plant https://www.crop.bayer.com.au/find‐crop‐solutions/by‐pest/diseases/ascochyta‐blight     

Mycobiota dysbiosis: a new nexus in intestinal tumorigenesis

While there is growing evidence that perturbation of the gut microbiota can result in a variety of pathologies including gut tumorigenesis, the influence of commensal fungi remains less clear. In this issue, Zhu et al (2021) show that mycobiota dysbiosis stimulates energy metabolism changes in subepithelial macrophages promoting colon cancer via enhancing innate lymphoid cell activity. These findings provide insights into a role of the gut flora in intestinal carcinogenesis and suggest opportunities for adjunctive antifungal or immunotherapeutic strategies to prevent colorectal cancer.Subject Categories: Cancer, Immunology, Metabolism

Recent work reports a role for the commensal gut flora in driving aberrant host immunity and malignant cytokine signaling.

There is growing evidence for an important role for the microbiota in influencing tumorigenesis (Helmink et al, 2019). It is now well documented that gut microbiota represents a highly diverse polymicrobial population of bacteria, fungi, viruses, and protozoa. Recent evidence highlights involvement of the bacterial component of the gut microbiota in protection or enhancement of colorectal tumorigenesis. In contrast, the importance of the mycobiota is less well understood although recently suggested to promote pancreatic oncogenesis and colitis‐associated colon cancer (CAC) (Wang et al, 2018; Aykut et al, 2019). Therefore, gut fungi may play a role in the development of other gastro‐intestinal cancer types, such as CRC. Notably, there is emerging evidence suggesting that mycobiota imbalance modulates immune cells and can trigger inflammatory bowel disease (IBD) (Richard & Sokol, 2019).Here, Zhu et al (2021) provide new insight into the association between mycobiota dysbiosis, immunomodulation, and tumorigenesis in the mouse gut (Fig 1).Open in a separate windowFigure 1Dectin‐3 deficiency induces fungal dysbiosis and tumorigenesis in mice by orchestrating immune cell metabolism and cytokine signalingIn the gut of wild‐type mice, the natural population of the commensal yeast Candida albicans is detected by the Dectin‐3 receptor located on the subepithelial macrophage cell surface. This recognition allows macrophages to maintain gut homeostasis by exerting an antifungal activity. In Dectin‐3‐deficient mice, the mycobiota becomes disrupted and aberrantly increased populations of C. albicans emerge. Elevated C. albicans load triggers increased glycolysis in macrophages and interleukin‐7 (IL‐7) secretion. Macrophage‐derived IL‐7 finally induces IL‐22 secretion by group‐3 innate lymphoid cells that in turn promote tumor cell proliferation in the gut epithelium.The current study (Zhu et al, 2021) is based on previous observations suggesting that human pathogenic fungi are recognized by the C‐type lectin receptor Dectin‐3. This led Zhu et al (2021) to test whether the mycobiota influenced gut tumor formation and is linked to immune recognition mediated by Dectin‐3. First, the authors demonstrated that mice lacking the Dectin‐3 receptor had increased colonic tumorigenesis in response to the azoxymethane (AOM) and dextran sodium sulfate (DSS). This was evident histologically in marked differences in tumor number, size, and burden in Dectin‐3‐deficient mice. Of note, immunohistochemical staining revealed that the lack of Dectin‐3 induced gut tumor formation by triggering epithelial cell proliferation rather than preventing cell apoptosis. In fact, first insight into the impact of microbes in CAC was suggested by the observation that co‐housed WT and Dectin‐3‐deficient mice displayed no difference in tumorigenesis. The pivotal role of the microbiota was then underlined in fecal transplantation experiments. Chemically induced germ‐free mice that received feces from Dectin‐3 tumor‐bearing mice displayed exacerbated tumor development compared to wild‐type controls. In addition, the fungal burden was specifically increased in tumor‐bearing Dectin‐3‐deficient animals. Deep profiling of the mycobiota alterations demonstrated an increase in a single yeast species, i.e., Candida albicans, that normally behaves as commensal in the gut (Papon et al, 2013; Wilson, 2019). Preliminary experiments suggested that the increased burden of C. albicans in Dectin‐3‐deficient tumor‐bearing mice is due to impaired antifungal killing by macrophages. Consistently, elevated C. albicans populations triggered glycolysis and inflammatory IL‐7 secretion from lamina propria macrophages, suggesting that Dectin‐3 deficiency‐induced fungal dysbiosis resulted in modulation of gut macrophage metabolism, promoting tumorigenesis. Exploring the molecular and cellular mechanisms that linked macrophage‐derived IL‐7 secretion and CRC development, Zhu et al (2021) showed in vitro that IL‐7 produced by subepithelial macrophages induced IL‐22 secretion by group‐3 innate lymphoid cells (ILC3s). In turn, up‐regulation of IL‐22 in Dectin‐3‐deficient mice contributed to the oncogenesis seen in these animals. Finally, a detailed analysis of tumor tissues collected from 172 patients with CRC showed correlation and poorer clinical outcome in patients with decreased expression of Dectin‐3, but increased expression of IL‐22 and mycobiota burden, although they did not directly link this to the presence of C. albicans in these patients.Overall, Zhu et al (2021) define a new cell paradigm linking mycobiota dysbiosis, macrophage energy metabolism, and innate lymphoid cell function to tumor development in the mouse gut. In this context, this study also sheds additional light on a new role of ILC3s, a recently described type of lymphoid effectors (Serafini et al, 2015). Indeed, ILC3s have been shown in the present article to act as cornerstone cells orchestrating cytokine‐regulated tumorigenesis in the gut. Beyond these pathophysiological considerations, the study opens up new opportunities for developing adjunctive antifungal or immunotherapeutic strategies for the prevention of high morbidity in CRC. Importantly, this enlightening article provides firm evidence that colonic C. albicans populations promote metabolic reprogramming in lamina propria macrophages and tumor cell formation. Metabolic reprogramming has been observed with other fungi, such as Aspergillus fumigatus, which induces metabolic rewiring of alveolar macrophages in the lung epithelium (Gonçalves et al, 2020). In line, the report by Zhu et al (2021) adds to previous work suggesting that mycobiota promotes pancreatic oncogenesis via activation of mannose‐binding lectins (Aykut et al, 2019). Mycobiota dysbiosis therefore stands out as an important new field of investigation in cancer research that is ripe for future exploration.