共查询到20条相似文献,搜索用时 15 毫秒
1.
Markus P Kummer Christina Ising Christiane Kummer Heela Sarlus Angelika Griep Ana VieiraSaecker Stephanie Schwartz Annett Halle Matthias Brückner Kristian Hndler Joachim L Schultze Marc Beyer Eicke Latz Michael T Heneka 《The EMBO journal》2021,40(24)
Chronic neuroinflammation is a pathogenic component of Alzheimer’s disease (AD) that may limit the ability of the brain to clear amyloid deposits and cellular debris. Tight control of the immune system is therefore key to sustain the ability of the brain to repair itself during homeostasis and disease. The immune‐cell checkpoint receptor/ligand pair PD‐1/PD‐L1, known for their inhibitory immune function, is expressed also in the brain. Here, we report upregulated expression of PD‐L1 and PD‐1 in astrocytes and microglia, respectively, surrounding amyloid plaques in AD patients and in the APP/PS1 AD mouse model. We observed juxtamembrane shedding of PD‐L1 from astrocytes, which may mediate ectodomain signaling to PD‐1‐expressing microglia. Deletion of microglial PD‐1 evoked an inflammatory response and compromised amyloid‐β peptide (Aβ) uptake. APP/PS1 mice deficient for PD‐1 exhibited increased deposition of Aβ, reduced microglial Aβ uptake, and decreased expression of the Aβ receptor CD36 on microglia. Therefore, ineffective immune regulation by the PD‐1/PD‐L1 axis contributes to Aβ plaque deposition during chronic neuroinflammation in AD. 相似文献
2.
Lian Fang Rui Feng Weiye Liang FangFang Liu Ganlan Bian Caiyong Yu Hongmin Guo Yihui Cao Mingkai Liu Jia Zuo Yinglong Peng Jie Zhao RuiXia Sun Jiajie Shan Jian Wang 《Journal of cellular and molecular medicine》2022,26(10):2908
Spermatogenesis is a cyclical process in which different generations of spermatids undergo a series of developmental steps at a fixed time and finally produce spermatids. Here, we report that overexpression of PD‐L1 (B7 homolog1) in the testis causes sperm developmental disorders and infertility in male mice, with severe malformation and sloughing during spermatid development, characterized by disorganized and collapsed seminiferous epithelium structure. PD‐L1 needs to be simultaneously expressed on Sertoli cells and spermatogonia to cause spermatogenesis failure. After that, we excluded the influence of factors such as the PD‐L1 receptor and humoral regulation, confirming that PD‐L1 has an intrinsic function to interact with PD‐L1. Studies have shown that PD‐L1 not only serves as a ligand but also plays a receptor‐like role in signal transduction. PD‐L1 interacts with PD‐L1 to affect the adhesive function of germ cells, causing malformation and spermatid sloughing. Taken together, these results indicate that PD‐L1 can interact with PD‐L1 to cause germ cell detachment and male infertility. 相似文献
3.
DeJun Zhang ZeMing Fu YingYuan Guo Fang Guo YiNing Wan GuoFang Guan 《Journal of cellular and molecular medicine》2023,27(1):113
A better understanding of the mechanisms underlying PD‐L1 aberrant expression in head and neck squamous cell carcinoma (HNSCC) will help reveal predictive biomarkers and overcome resistance to treatment. In this study, the prognostic significance of PD‐L1 in forty‐five HNSCC archival samples was determined by qRT‐PCR. The biological function associated with malignant behaviour was assessed by PD‐L1 depletion, miR‐382‐3p re‐expression and regulation of circ_0000052. The interactions of PD‐L1‐miRNA and miRNA‐circRNA were determined by qRT‐PCR, Western blot analysis, dual‐luciferase reporter assays and RNA immunoprecipitation assays. PD‐L1 was highly expressed in patient samples and cancer cell lines. Higher levels of PD‐L1 were associated with patient recurrences and play a pivotal role in regulating cell proliferation, migration, invasion, clonogenicity and apoptosis. In addition to demonstrating that the IFN‐γ/JAK2/STAT1 signalling pathway can induce PD‐L1 overexpression in HNSCC, a novel mechanism by which upregulated circ_0000052 mediates PD‐L1 overexpression was also demonstrated. To do this, circ_0000052 competitively binds to miR‐382‐3p and alleviates its repression of PD‐L1. This leads to overexpression of PD‐L1, causing the aggressiveness of the cells. Our data demonstrate that circ_0000052 is oncogenic, and the circ_0000052/miR‐382‐3p/PD‐L1 axis is critical in HNSCC progression. The manipulation of circRNAs/miRNAs in combination with anti‐PD‐L1 therapy may improve personalized disease management. 相似文献
4.
5.
Rui Zhang Ziqi Meng Xuwei Wu Meihua Zhang Zhengri Piao Tiefeng Jin 《Journal of cellular and molecular medicine》2022,26(23):5872
PD‐L1 is closely related to the immune escape process of tumour cells, and targeted PD‐L1 clinical immunotherapy has been implemented. However, whether PD‐L1 is involved in TAM/M2 polarization in the TME of NSCLC and its specific mechanism remain unclear. In order to clarify the specific role of PD‐L1 in NSCLC and to seek new treatments for NSCLC, we designed a series of experimental studies. After constructing the co‐culture system and conditioned medium system, the proliferation, apoptosis, metastasis, angiogenesis, EMT process and stemness of NSCLC were detected by MTT, flow cytometry, Transwell, endothelial cell tube formation and western blot assays. The results showed that αPD‐L1 reversed TAM/M2 polarization by suppressing STAT3 phosphorylation in TAM/M2, therapy inhibiting NSCLC cell migration, angiogenesis, EMT process and stemness. However, αPD‐L1 had no effect on the proliferation and apoptosis abilities of NSCLC cells. In vivo experiments showed that αPD‐L1 inhibited lung metastasis of NSCLC and reversed TAM/M2 polarization in TME. The study investigates the mechanism by which PD‐L1 regulates TAMs polarization in TME and promotes malignant progression of NSCLC, providing a new theoretical basis for PD‐L1 targeted therapy of NSCLC. 相似文献
6.
Qigu Yao Lihu Gu Rong Su Bangsheng Chen Hongcui Cao 《Journal of cellular and molecular medicine》2020,24(22):13494
Treatment of multiple malignant solid tumours with programmed death (PD)‐1/PD ligand (PD‐L) 1 inhibitors has been reported. However, the efficacy and immune adverse effects of combination therapies are controversial. This meta‐analysis was performed with PubMed, Web of Science, Medline, EMBASE and Cochrane Library from their inception until January 2020. Random‐effect model was adopted because of relatively high heterogeneity. We also calculated hazard ratio (HR) of progression‐free survival (PFS), overall survival (OS) and risk ratio (RR) of adverse events (AEs), the incidence of grade 3‐5 AEs by tumour subgroup, therapeutic schedules and therapy lines. Nineteen articles were selected using the search strategy for meta‐analysis. Combined PD‐1/PD‐L1 inhibitors prolonged OS and PFS (HR 0.72, P < 0.001) and (HR 0.66, P < 0.001). In addition, incidence of all‐grade and grade 3‐5 AEs was not significant in the two subgroup analyses (HR 1.01, P = 0.31) and (HR 1.10, P = 0.07), respectively. Our meta‐analysis indicated that combination therapy with PD‐1/PD‐L1 inhibitors had greater clinical benefits and adverse events were not increased significantly. 相似文献
7.
Programmed death‐ligand 1 (PD‐L1) is involved in immunosuppression in variety of tumours. Regulatory B cells (Bregs) are critical immune regulatory cells, and it has been demonstrated that the number of regulatory B cells in patients with acute myeloid leukaemia (AML) is much higher than that in healthy donors (HDs), which is linked to a poor prognosis. This study aimed to determine whether increased expression of PD‐L1, including in Bregs, is associated with a worse prognosis in individuals with AML. The proportion of Bregs, PD‐L1 expression in Bregs and PD‐1 expression in T cells were determined using flow cytometry using patient samples from 21 newly diagnosed AML patients at different stages of treatment and 25 HDs. We confirmed PD‐L1 expression in Bregs, and PD‐1 expression in CD3+CD4+T cells in bone marrow and peripheral blood samples from AML patients was higher than that in samples from HDs. The complete remission (CR) and progression‐free survival (PFS) of Bregs with high PD‐L1 expression were significantly decreased following induction chemotherapy. PD‐L1 expression is indeed increased in Bregs from individuals with AML, and high PD‐L1 expression is related to a poor prognosis. 相似文献
8.
Low frequency of durable responses in patients treated with immune checkpoint inhibitors (ICIs) demands for taking complementary strategies in order to boost immune responses against cancer. Transforming growth factor‐β (TGF‐β) is a multi‐tasking cytokine that is frequently expressed in tumours and acts as a critical promoter of tumour hallmarks. TGF‐β promotes an immunosuppressive tumour microenvironment (TME) and defines a bypass mechanism to the ICI therapy. A number of cells within the stroma of tumour are influenced from TGF‐β activity. There is also evidence of a relation between TGF‐β with programmed death‐ligand 1 (PD‐L1) expression within TME, and it influences the efficacy of anti‐programmed death‐1 receptor (PD‐1) or anti‐PD‐L1 therapy. Combination of TGF‐β inhibitors with anti‐PD(L)1 has come to the promising outcomes, and clinical trials are under way in order to use agents with bifunctional capacity and fusion proteins for bonding TGF‐β traps with anti‐PD‐L1 antibodies aiming at reinvigorating immune responses and promoting persistent responses against advanced stage cancers, especially tumours with immunologically cold ecosystem. 相似文献
9.
Lingling Wang Lujing Wu Zhouting Zhu Qiong Zhang Wanyu Li Gwendolyn Michelle Gonzalez Yinsheng Wang Tariq M Rana 《The EMBO journal》2023,42(2)
Adenosine N6‐methylation (m6A) and N6,2′‐O‐dimethylation (m6Am) are regulatory modifications of eukaryotic mRNAs. m6Am formation is catalyzed by the methyl transferase phosphorylated CTD‐interacting factor 1 (PCIF1); however, the pathophysiological functions of this RNA modification and PCIF1 in cancers are unclear. Here, we show that PCIF1 expression is upregulated in colorectal cancer (CRC) and negatively correlates with patient survival. CRISPR/Cas9‐mediated depletion of PCIF1 in human CRC cells leads to loss of cell migration, invasion, and colony formation in vitro and loss of tumor growth in athymic mice. Pcif1 knockout in murine CRC cells inhibits tumor growth in immunocompetent mice and enhances the effects of anti‐PD‐1 antibody treatment by decreasing intratumoral TGF‐β levels and increasing intratumoral IFN‐γ, TNF‐α levels, and tumor‐infiltrating natural killer cells. We further show that PCIF1 modulates CRC growth and response to anti‐PD‐1 in a context‐dependent mechanism with PCIF1 directly targeting FOS, IFITM3, and STAT1 via m6Am modifications. PCIF1 stabilizes FOS mRNA, which in turn leads to FOS‐dependent TGF‐β regulation and tumor growth. While during immunotherapy, Pcif1‐Fos‐TGF‐β, as well as Pcif1‐Stat1/Ifitm3‐IFN‐γ axes, contributes to the resistance of anti‐PD‐1 therapy. Collectively, our findings reveal a role of PCIF1 in promoting CRC tumorigenesis and resistance to anti‐PD‐1 therapy, supporting that the combination of PCIF1 inhibition with anti‐PD‐1 treatment is a potential therapeutic strategy to enhance CRC response to immunotherapy. Finally, we developed a lipid nanoparticles (LNPs) and chemically modified small interfering RNAs (CMsiRNAs)‐based strategy to silence PCIF1 in vivo and found that this treatment significantly reduced tumor growth in mice. Our results therefore provide a proof‐of‐concept for tumor growth suppression using LNP‐CMsiRNA to silence target genes in cancer. 相似文献
10.
Kefang Liu Shuguang Tan Wanjun Jin Jiawei Guan Qingling Wang Huan Sun Jianxun Qi Jinghua Yan Yan Chai Zhongfu Wang Chuxia Deng George F Gao 《EMBO reports》2020,21(12)
PD‐1 is a highly glycosylated inhibitory receptor expressed mainly on T cells. Targeting of PD‐1 with monoclonal antibodies (MAbs) to block the interaction with its ligand PD‐L1 has been successful for the treatment of multiple tumors. However, polymorphisms at N‐glycosylation sites of PD‐1 exist in the human population that might affect antibody binding, and dysregulated glycosylation has been observed in the tumor microenvironment. Here, we demonstrate varied N‐glycan composition in PD‐1, and show that the binding affinity of camrelizumab, a recently approved PD‐1‐specific MAb, to non‐glycosylated PD‐1 proteins from E. coli is substantially decreased compared with glycosylated PD‐1. The structure of the camrelizumab/PD‐1 complex reveals that camrelizumab mainly utilizes its heavy chain to bind to PD‐1, while the light chain sterically inhibits the binding of PD‐L1 to PD‐1. Glycosylation of asparagine 58 (N58) promotes the interaction with camrelizumab, while the efficiency of camrelizumab to inhibit the binding of PD‐L1 is substantially reduced for glycosylation‐deficient PD‐1. These results increase our understanding of how glycosylation affects the activity of PD‐1‐specific MAbs during immune checkpoint therapy. 相似文献
11.
Xiaodong Li Yichang Wang Wei Wu Jianyang Xiang Maode Wang Hai Yu 《Journal of cellular and molecular medicine》2022,26(13):3736
Gliomas, as the most lethal and malignant brain tumours in adults, remain a major challenge worldwide. DNA damage and repair‐related genes (DDRRGs) appear to play a significant role in gliomas, but the studies of DDRRGs are still insufficient. Herein, we systematically explored and analysed 1547 DDRRGs in 938 glioma samples from TCGA and CGGA datasets. Using least absolute shrinkage and selection operator (LASSO) Cox regression analysis, we identified a 16‐DDRRG signature, characterized by high‐risk and low‐risk patterns. This risk model harbours robust predictive capability for overall survival of glioma patients. We found the high‐risk score is strongly associated with well‐known malignant features of gliomas, such as the mesenchymal subtype, IDH‐wildtype, 1p/19q non‐codeletion and MGMT promoter unmethylated status. In addition, we found that the high‐risk score is also linked with multiple oncogenic pathways and therapeutic resistance. Significantly, we found the high‐risk group has higher enrichment of immunosuppressive cells (M2‐type macrophages, Tregs and MDSCs) and immune inhibition biomarkers (PD‐1, PD‐L1 and CTLA‐4). Lastly, we proved that SMC4, which has the highest positive regression coefficient in our risk model, is strongly linked with malignant progression and TMZ resistance of gliomas in a E2F1‐dependent manner. 相似文献
12.
David Hoffmann Stefan Mereiter Yoo Jin Oh Vanessa Monteil Elizabeth Elder Rong Zhu Daniel Canena Lisa Hain Elisabeth Laurent Clemens GrünwaldGruber Miriam Klausberger Gustav Jonsson Max J Kellner Maria Novatchkova Melita Ticevic Antoine Chabloz Gerald Wirnsberger Astrid Hagelkruys Friedrich Altmann Lukas Mach Johannes Stadlmann Chris Oostenbrink Ali Mirazimi Peter Hinterdorfer Josef M Penninger 《The EMBO journal》2021,40(19)
New SARS‐CoV‐2 variants are continuously emerging with critical implications for therapies or vaccinations. The 22 N‐glycan sites of Spike remain highly conserved among SARS‐CoV‐2 variants, opening an avenue for robust therapeutic intervention. Here we used a comprehensive library of mammalian carbohydrate‐binding proteins (lectins) to probe critical sugar residues on the full‐length trimeric Spike and the receptor binding domain (RBD) of SARS‐CoV‐2. Two lectins, Clec4g and CD209c, were identified to strongly bind to Spike. Clec4g and CD209c binding to Spike was dissected and visualized in real time and at single‐molecule resolution using atomic force microscopy. 3D modelling showed that both lectins can bind to a glycan within the RBD‐ACE2 interface and thus interferes with Spike binding to cell surfaces. Importantly, Clec4g and CD209c significantly reduced SARS‐CoV‐2 infections. These data report the first extensive map and 3D structural modelling of lectin‐Spike interactions and uncovers candidate receptors involved in Spike binding and SARS‐CoV‐2 infections. The capacity of CLEC4G and mCD209c lectins to block SARS‐CoV‐2 viral entry holds promise for pan‐variant therapeutic interventions. 相似文献
13.
Jamie A. G. Hamilton Miyoung Y. Lee Rae Hunter Raira S. Ank Jamie Y. Story Ganesh Talekar Talia Sisroe Dov B. Ballak Andrew Fedanov Christopher C. Porter Elan Z. Eisenmesser Charles A. Dinarello Sunil S. Raikar James DeGregori Curtis J. Henry 《Aging cell》2021,20(2)
Aging‐associated declines in innate and adaptive immune responses are well documented and pose a risk for the growing aging population, which is predicted to comprise greater than 40 percent of the world''s population by 2050. Efforts have been made to improve immunity in aged populations; however, safe and effective protocols to accomplish this goal have not been universally established. Aging‐associated chronic inflammation is postulated to compromise immunity in aged mice and humans. Interleukin‐37 (IL‐37) is a potent anti‐inflammatory cytokine, and we present data demonstrating that IL‐37 gene expression levels in human monocytes significantly decline with age. Furthermore, we demonstrate that transgenic expression of interleukin‐37 (IL‐37) in aged mice reduces or prevents aging‐associated chronic inflammation, splenomegaly, and accumulation of myeloid cells (macrophages and dendritic cells) in the bone marrow and spleen. Additionally, we show that IL‐37 expression decreases the surface expression of programmed cell death protein 1 (PD‐1) and augments cytokine production from aged T‐cells. Improved T‐cell function coincided with a youthful restoration of Pdcd1, Lat, and Stat4 gene expression levels in CD4+ T‐cells and Lat in CD8+ T‐cells when aged mice were treated with recombinant IL‐37 (rIL‐37) but not control immunoglobin (Control Ig). Importantly, IL‐37‐mediated rejuvenation of aged endogenous T‐cells was also observed in aged chimeric antigen receptor (CAR) T‐cells, where improved function significantly extended the survival of mice transplanted with leukemia cells. Collectively, these data demonstrate the potency of IL‐37 in boosting the function of aged T‐cells and highlight its therapeutic potential to overcome aging‐associated immunosenescence. 相似文献
14.
Swetha Lankipalli Mahadeva Swamy H S Deepak Selvam Dibyendu Samanta Deepak Nair Udupi A. Ramagopal 《Protein science : a publication of the Protein Society》2021,30(9):1958
T‐cell co‐stimulation through CD28/CTLA4:B7‐1/B7‐2 axis is one of the extensively studied pathways that resulted in the discovery of several FDA‐approved drugs for autoimmunity and cancer. However, many aspects of the signaling mechanism remain elusive, including oligomeric association and clustering of B7‐2 on the cell surface. Here, we describe the structure of the IgV domain of B7‐2 and its cryptic association into 1D arrays that appear to represent the pre‐signaling state of B7‐2 on the cell membrane. Super‐resolution microscopy experiments on heterologous cells expressing B7‐2 and B7‐1 suggest, B7‐2 form relatively elongated and larger clusters compared to B7‐1. The sequence and structural comparison of other B7 family members, B7‐1:CTLA4 and B7‐2:CTLA‐4 complex structures, support our view that the observed B7‐2 1D zipper array is physiologically important. This observed 1D zipper‐like array also provides an explanation for its clustering, and upright orientation on the cell surface, and avoidance of spurious signaling. 相似文献
15.
Leonardo Antnio Fernandes Anderson Albino Gomes Beatriz Gomes Guimares Maria de Lourdes Borba Magalhes Partha Ray Gustavo Felippe da Silva 《Protein science : a publication of the Protein Society》2022,31(6)
The binding of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) spike protein to the angiotensin‐converting enzyme 2 (ACE2) receptor expressed on the host cells is a critical initial step for viral infection. This interaction is blocked through competitive inhibition by soluble ACE2 protein. Therefore, developing high‐affinity and cost‐effective ACE2 mimetic ligands that disrupt this protein–protein interaction is a promising strategy for viral diagnostics and therapy. We employed human and plant defensins, a class of small (2–5 kDa) and highly stable proteins containing solvent‐exposed alpha‐helix, conformationally constrained by two disulfide bonds. Therefore, we engineered the amino acid residues on the constrained alpha‐helix of defensins to mimic the critical residues on the ACE2 helix 1 that interact with the SARS‐CoV‐2 spike protein. The engineered proteins (h‐deface2, p‐deface2, and p‐deface2‐MUT) were soluble and purified to homogeneity with a high yield from a bacterial expression system. The proteins demonstrated exceptional thermostability (Tm 70.7°C), high‐affinity binding to the spike protein with apparent K d values of 54.4 ± 11.3, 33.5 ± 8.2, and 14.4 ± 3.5 nM for h‐deface2, p‐deface2, and p‐deface2‐MUT, respectively, and were used in a diagnostic assay that detected SARS‐CoV‐2 neutralizing antibodies. This work addresses the challenge of developing helical ACE2 mimetics by demonstrating that defensins provide promising scaffolds to engineer alpha‐helices in a constrained form for designing of high‐affinity ligands. 相似文献
16.
Sheetal Kaw Swetha Ananth Nikolaos Tsopoulidis Katharina Morath Bahar M Coban Ralph Hohenberger Olcay C Bulut Florian Klein Bettina Stolp Oliver T Fackler 《The EMBO journal》2020,39(24)
Failures to produce neutralizing antibodies upon HIV‐1 infection result in part from B‐cell dysfunction due to unspecific B‐cell activation. How HIV‐1 affects antigen‐specific B‐cell functions remains elusive. Using an adoptive transfer mouse model and ex vivo HIV infection of human tonsil tissue, we found that expression of the HIV‐1 pathogenesis factor NEF in CD4 T cells undermines their helper function and impairs cognate B‐cell functions including mounting of efficient specific IgG responses. NEF interfered with T cell help via a specific protein interaction motif that prevents polarized cytokine secretion at the T‐cell–B‐cell immune synapse. This interference reduced B‐cell activation and proliferation and thus disrupted germinal center formation and affinity maturation. These results identify NEF as a key component for HIV‐mediated dysfunction of antigen‐specific B cells. Therapeutic targeting of the identified molecular surface in NEF will facilitate host control of HIV infection. 相似文献
17.
Jian Lei Yue MaLauer Yinze Han Matthias Thoms Robert Buschauer Joerg Jores Volker Thiel Roland Beckmann Wen Deng Heinrich Leonhardt Rolf Hilgenfeld Albrecht von Brunn 《The EMBO journal》2021,40(11)
The ongoing outbreak of severe acute respiratory syndrome (SARS) coronavirus 2 (SARS‐CoV‐2) demonstrates the continuous threat of emerging coronaviruses (CoVs) to public health. SARS‐CoV‐2 and SARS‐CoV share an otherwise non‐conserved part of non‐structural protein 3 (Nsp3), therefore named as “SARS‐unique domain” (SUD). We previously found a yeast‐2‐hybrid screen interaction of the SARS‐CoV SUD with human poly(A)‐binding protein (PABP)‐interacting protein 1 (Paip1), a stimulator of protein translation. Here, we validate SARS‐CoV SUD:Paip1 interaction by size‐exclusion chromatography, split‐yellow fluorescent protein, and co‐immunoprecipitation assays, and confirm such interaction also between the corresponding domain of SARS‐CoV‐2 and Paip1. The three‐dimensional structure of the N‐terminal domain of SARS‐CoV SUD (“macrodomain II”, Mac2) in complex with the middle domain of Paip1, determined by X‐ray crystallography and small‐angle X‐ray scattering, provides insights into the structural determinants of the complex formation. In cellulo, SUD enhances synthesis of viral but not host proteins via binding to Paip1 in pBAC‐SARS‐CoV replicon‐transfected cells. We propose a possible mechanism for stimulation of viral translation by the SUD of SARS‐CoV and SARS‐CoV‐2. 相似文献
18.
Hanna Kratzat Timur MackensKiani Michael Ameismeier Mia Potocnjak Jingdong Cheng Estelle Dacheux Abdelkader Namane Otto Berninghausen Franz Herzog Micheline FromontRacine Thomas Becker Roland Beckmann 《The EMBO journal》2021,40(1)
In eukaryotic translation, termination and ribosome recycling phases are linked to subsequent initiation of a new round of translation by persistence of several factors at ribosomal sub‐complexes. These comprise/include the large eIF3 complex, eIF3j (Hcr1 in yeast) and the ATP‐binding cassette protein ABCE1 (Rli1 in yeast). The ATPase is mainly active as a recycling factor, but it can remain bound to the dissociated 40S subunit until formation of the next 43S pre‐initiation complexes. However, its functional role and native architectural context remains largely enigmatic. Here, we present an architectural inventory of native yeast and human ABCE1‐containing pre‐initiation complexes by cryo‐EM. We found that ABCE1 was mostly associated with early 43S, but also with later 48S phases of initiation. It adopted a novel hybrid conformation of its nucleotide‐binding domains, while interacting with the N‐terminus of eIF3j. Further, eIF3j occupied the mRNA entry channel via its ultimate C‐terminus providing a structural explanation for its antagonistic role with respect to mRNA binding. Overall, the native human samples provide a near‐complete molecular picture of the architecture and sophisticated interaction network of the 43S‐bound eIF3 complex and the eIF2 ternary complex containing the initiator tRNA. 相似文献
19.
Ni Zeng Christophe M Capelle Alexandre Baron Takumi Kobayashi Severine Cire Vera Tslaf Cathy Leonard Djalil Coowar Haruhiko Koseki Astrid M Westendorf Jan Buer Dirk Brenner Rejko Krüger Rudi Balling Markus Ollert Feng Q Hefeng 《EMBO reports》2022,23(3)
Decline in immune function during aging increases susceptibility to different aging‐related diseases. However, the underlying molecular mechanisms, especially the genetic factors contributing to imbalance of naïve/memory T‐cell subpopulations, still remain largely elusive. Here, we show that loss of DJ‐1 encoded by PARK7/DJ‐1, causing early‐onset familial Parkinson’s disease (PD), unexpectedly diminished signs of immunoaging in T‐cell compartments of both human and mice. Compared with two gender‐matched unaffected siblings of similar ages, the index PD patient with DJ‐1 deficiency showed a decline in many critical immunoaging features, including almost doubled non‐senescent T cells. The observation was further consolidated by the results in 45‐week‐old DJ‐1 knockout mice. Our data demonstrated that DJ‐1 regulates several immunoaging features via hematopoietic‐intrinsic and naïve‐CD8‐intrinsic mechanisms. Mechanistically, DJ‐1 depletion reduced oxidative phosphorylation (OXPHOS) and impaired TCR sensitivity in naïve CD8 T cells at a young age, accumulatively leading to a reduced aging process in T‐cell compartments in older mice. Our finding suggests an unrecognized critical role of DJ‐1 in regulating immunoaging, discovering a potent target to interfere with immunoaging‐ and aging‐associated diseases. 相似文献