Organismal Aging and Oxidants beyond Macromolecules Damage

The relationship between oxidants and organismal aging was first articulated through the free radical theory of aging. One of the major predictions of the free radical theory of aging is that oxidative stress shortens organisms’ lifespan because of an increased level of oxidants, which are damaging to macromolecules. However, challenging the role of oxidants in age‐related diseases, there is now sufficient evidence that antioxidant supplements do not provide significant health benefits. Interestingly, in addition to an increase in oxidant‐mediated macromolecules damage, there is convincing experimental data to support the role of senescent cells in the process of aging. Here, the current knowledge regarding the role of oxidants and cellular senescence in organismal aging is reviewed and it is proposed that, in addition to the role of oxidants as inducers of macromolecular damage, oxidants may also function as regulators of signaling pathways involved in the establishment of cellular senescence. If this role for oxidants is established, it may be necessary to modify the free radical theory of aging from “Organisms age because cells accumulate reactive oxygen species‐dependent damage over time” to: “Organisms age because cells accumulate oxidants’‐dependent damage and oxidants’‐dependent senescent characteristics over time.”     

PagR mediates the precise regulation of Salmonella pathogenicity island 2 gene expression in response to magnesium and phosphate signals in Salmonella Typhimurium

To establish systemic infections, Salmonella enterica serovar Typhimurium (S. Typhimurium) requires Salmonella pathogenicity island 2 (SPI‐2) to survive and replicate within macrophages. High expression of many SPI‐2 genes during the entire intracellular growth period within macrophages is essential, as it contributes to the formation of Salmonella‐containing vacuole and bacterial replication. However, the regulatory mechanisms underlying the sustained induction of SPI‐2 within macrophages are not fully understood. Here, we revealed a time‐dependent regulation of SPI‐2 expression mediated by a novel regulator PagR (STM2345) in response to the low Mg²⁺ and low phosphate (P_i) signals, which ensured the high induction of SPI‐2 during the entire intramacrophage growth period. Deletion of pagR results in reduced bacterial replication in macrophages and attenuation of systemic virulence in mice. The effects of pagR on virulence are dependent on upregulating the expression of slyA, a regulator of SPI‐2. At the early (0–4 hr) and later (after 4 hr) stage post‐infection of macrophages, pagR is induced by the low P_i via PhoB/R two‐component systems and low Mg²⁺ via PhoP/Q systems, respectively. Collectively, our findings revealed that the PagR‐mediated regulatory mechanism contributes to the precise and sustained activation of SPI‐2 genes within macrophages, which is essential for S. Typhimurium systemic virulence.     

Protein kinases phosphorylate long disordered regions in intrinsically disordered proteins

Phosphorylation is a major post‐translational modification that plays a central role in signaling pathways. Protein kinases phosphorylate substrates (phosphoproteins) by adding phosphate at Ser/Thr or Tyr residues (phosphosites). A large amount of data identifying and describing phosphosites in phosphoproteins has been reported but the specificity of phosphorylation is not fully resolved. In this report, data of kinase‐substrate pairs identified by the Kinase‐Interacting Substrate Screening (KISS) method were used to analyze phosphosites in intrinsically disordered regions (IDRs) of intrinsically disordered proteins. We compared phosphorylated and nonphosphorylated IDRs and found that the phosphorylated IDRs were significantly longer than nonphosphorylated IDRs. The phosphorylated IDR is often the longest IDR (71%) in a phosphoprotein when only a single phosphosite exists in the IDR, and when the phosphoprotein has multiple phosphosites in an IDR(s), the phosphosites are primarily localized in a single IDR (78%) and this IDR is usually the longest one (81%). We constructed a stochastic model of phosphorylation to estimate the effect of IDR length. The model that accounted for IDR length produced more realistic results when compared with a model that excluded the IDR length. We propose that the IDR length is a significant determinant for locating kinase phosphorylation sites in phosphoproteins.     

Rcs双组分调节系统对细菌环境应答的分子调控研究进展

荚膜异多糖酸合成调节(Regulator of Capsule Synthesis,Rcs)系统是存在于许多肠杆菌科细菌中非典型的双组分调节系统,由3种核心蛋白(跨膜感应激酶RcsC、跨膜蛋白RcsD和响应调节剂RcsB)及多种辅助蛋白共同构成。Rcs系统能整合环境信号、调节基因表达并改变细菌的生理行为。近年来,对细菌Rcs系统环境应答机制的探索成为一个新的研究热点。本文重点综述Rcs系统上游信号的感知与传导、Rcs系统调节的下游靶基因及其生命现象,以期能增进对细菌Rcs系统的认识,同时为细菌的安全控制、感染预防和治疗新方案的开发提供参考。     

Biomolecular condensates in membrane receptor signaling

Clustering is a prominent feature of receptors at the plasma membrane (PM). It plays an important role in signaling. Liquid–liquid phase separation (LLPS) of proteins is emerging as a novel mechanism underlying the observed clustering. Receptors/transmembrane signaling proteins can be core components essential for LLPS (such as LAT or nephrin) or clients enriched at the phase-separated condensates (for example, at the postsynaptic density or at tight junctions). Condensate formation has been shown to regulate signaling in multiple ways, including by increasing protein binding avidity and by modulating the local biochemical environment. In moving forward, it is important to study protein LLPS at the PM of living cells, its interplay with other factors underlying receptor clustering, and its signaling and functional consequences.     

ERF转录因子调控生物胁迫反应的研究进展

ERF家族是植物所特有的APETALA2/乙烯响应因子(APETALA2/ethylene-responsive factor,AP2/ERF)转录因子家族的一个主要亚家族,其成员结构特点是仅含有1个58-60个氨基酸组成的AP2/ERF结构域。有关该家族成员的大多数研究集中在与寒、旱等非生物胁迫方面,最近越来越多的研究表明ERF在植物抵御病虫侵害等生物胁迫方面也发挥着重要作用。ERF亚家族成员通过结合下游互作基因启动子区域的GCC box元件,从而激活或抑制这些病程相关基因的表达。同时ERFs参与水杨酸(salicylic acid,SA)、茉莉酸(jasmonic acid,JA)、乙烯(ethylene,ET)及过氧化氢(H2O2)等多种激素的信号途径,通过相互促进/拮抗高效协调体内不同激素抵御病原菌的入侵,提高植物的抗病、抗虫性。本文综述了ERF转录因子的结构功能特点、在不同植物抗生物胁迫中的调控方式,以及其通过协调不同激素信号途径相互作用来提高植物抗病虫的最新研究进展,并对其应用前景进行了展望。     

基因治疗慢病毒载体的转导增强策略*

基于慢病毒载体的体外基因治疗已在临床试验中取得良好的效果,有望治愈一些造血系统的单基因遗传病。通过提高靶细胞转导效率和减少转导中病毒载体量,基因治疗有效性、安全性和成本都可以得到改善。不同包膜糖蛋白伪型慢病毒载体通过与细胞膜表面的不同受体结合,促进病毒黏附和入胞,增强不同靶细胞的病毒转导效率。此外病毒转导增强剂可以在病毒进入细胞过程或进入后发挥作用,在提高转导效率的同时使靶转导基因在体内长期稳定表达。通过对这两类方法的总结回顾,旨在为慢病毒载体的转导效率提供新的优化策略,使基因治疗得到更广泛的应用。     

Plant plasma membrane‐resident receptors: Surveillance for infections and coordination for growth and development

As sessile organisms, plants are exposed to pathogen invasions and environmental fluctuations. To overcome the challenges of their surroundings, plants acquire the potential to sense endogenous and exogenous cues, resulting in their adaptability. Hence, plants have evolved a large collection of plasma membrane-resident receptors, including RECEPTOR-LIKE KINASEs(RLKs) and RECEPTOR-LIKE PROTEINs(RLPs) to perceive those signals and regulate plant growth,development, and immunity. The ability of RLKs and RLPs to recognize distinct ligands relies on diverse categories of extracellular domains evolved. Co-regulatory receptors are often required to associate with RLKs and RLPs to facilitate cellular signal transduction. RECEPTOR-LIKE CYTOPLASMIC KINASEs(RLCKs) also associate with the complex, bifurcating the signal to key signaling hubs, such as MITOGEN-ACTIVATED PROTEIN KINASE(MAPK) cascades, to regulate diverse biological processes. Here, we discuss recent knowledge advances in understanding the roles of RLKs and RLPs in plant growth, development, and immunity, and their connection with co-regulatory receptors, leading to activation of diverse intracellular signaling pathways.