Managing stress granule disassembly with ubiquitin and its cousin.
Managing stress granule disassembly with ubiquitin and its cousin.
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DOI：
10.1038/s41392-021-00782-2
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发表时间：
2021-11-11
影响因子：
39.3
通讯作者：
Müller S
中科院分区：
文献类型：
--
作者：
Müller S
最近，麦克斯韦等1揭示了泛素化在热应激恢复后应激颗粒（SG）解体中的关键作用。生物体持续暴露于内源性或环境压力。基因毒性应激危及DNA完整性，而蛋白毒性应激导致蛋白质稳态（proteostasis）失衡。遗传毒性损伤激活DNA损伤反应途径，阻止细胞周期进程并启动DNA修复。蛋白质质量控制（PQC）系统反过来保护蛋白质组的完整性，并为压力释放后细胞活动的重新启动做好准备。基因组和蛋白质组完整性途径都是由泛素信号转导和泛素-蛋白酶体系统（UPS）协调的。在这里，我们强调了泰勒实验室最近的工作，为细胞如何利用泛素系统从热应激中恢复提供了新的见解。1，2蛋白质稳态是通过一个平衡蛋白质合成、折叠、运输和处置的途径网络来实现的。蛋白毒性应激干扰这些过程的平衡，并且通常诱导新生和成熟蛋白质的错误折叠，这最终可导致它们的功能丧失或触发毒性蛋白质聚集体的形成。神经退行性疾病是蛋白质错误折叠疾病（又名蛋白质病）的主要例子，其中蛋白质聚集体损害关键的细胞功能并对细胞、组织和器官造成不可逆的损伤。作为防止蛋白质错误折叠的一条防线，伴侣系统被激活。作为第二条线，错误折叠的蛋白质被自噬体/溶酶体或UPS清除。剪接、核质转运和蛋白质合成的抑制作为一种额外的保护机制，通过避免进一步流入过载的蛋白质稳态系统来维持应激下的蛋白质稳态。翻译的限制与不同的胞质核糖核蛋白缩合物（称为SG）的形成密切相关。SG形成是由翻译起始停滞时产生的无核糖体mRNA的积累触发的。这些mRNA与翻译因子和其他RNA结合蛋白（RBP）一起在SG中的瞬时储存确保了细胞在应激期间的存活，并使SG在从应激中恢复后能够快速分解和翻译重新启动。重要的是，受损的SG分解与一些神经退行性疾病有关，包括肌萎缩侧索硬化症和额颞叶痴呆。已经确定的是，在对蛋白毒性应激的响应中，UPS通过去除错误折叠的蛋白质而作为主要的PQC系统起作用。因此，泛素化强烈诱导热或氧化应激反应。然而，在响应不同的刺激进行泛素化的蛋白质的特定子集仍然在很大程度上难以捉摸。此外，除了错误折叠的蛋白质的处置之外，泛素化对应激恢复的贡献还没有很好的理解。特别是，在SG的动力学中的泛素化的作用仍然存在争议。在经典的泛素化途径中，泛素通过酶级联反应共价结合到靶蛋白的赖氨酸（K）残基上，该酶级联反应由E1激活酶、E2结合酶和E3连接酶组成。泛素化可以形成不同类型的赖氨酸连接的聚合物链，其触发不同的下游过程。用K48链标记的蛋白质通常靶向蛋白酶体进行蛋白水解降解，而其他链类型介导蛋白酶体独立的非蛋白水解信号传导功能，例如介导蛋白酶体的K63连接链。
Recently, Maxwell et al. 1 revealed a critical function of ubiquitylation in stress granule (SG) disassembly upon recovery from heat stress. Organisms are continuously exposed to endogenous or environmental stress. Genotoxic stress endangers DNA integrity, whereas proteotoxic stress causes an imbalance in protein homeostasis (proteostasis). Genotoxic insults activate DNA damage response pathways that halt the cell-cycle progression and initiate DNA repair. Protein quality control (PQC) systems in turn safeguard the integrity of the proteome and prepare for the restart of cellular activities upon stress release. Both genome and proteome integrity pathways are orchestrated by ubiquitin signaling and the ubiquitin-proteasome system (UPS). Here, we highlight very recent elegant recent work by the Taylor laboratory providing novel insight into how cells exploit the ubiquitin system for recovery from heat stress. 1, 2 Proteostasis is accomplished by a network of pathways that balance protein synthesis, folding, transport, and disposal. Proteotoxic stress disturbs the equilibrium of these processes and typically induces the misfolding of nascent and mature proteins, which can ultimately lead to their loss of function or trigger the formation of toxic protein aggregates. Neurodegenerative diseases are prime examples of protein misfolding diseases (aka proteinopathies), in which protein aggregates impair critical cellular functions and cause irreversible damage to cells, tissues, and organs. As one line of defense against protein misfolding, chaperone systems are activated. As a second line, misfolded proteins are cleared by the autophagosome/lysosome or the UPS. The inhibition of splicing, nucleocytoplasmic transport, and protein synthesis serves as an additional safeguard mechanism for maintaining protein homeostasis under stress by avoiding further influx into the overloaded proteostasis systems. The limitation of translation is tightly linked to the formation of distinct cytosolic ribonucleoprotein condensates, termed SGs. SG formation is triggered by the accumulation of ribosome-free mRNAs generated upon stalling of translation initiation. The transient storage of these mRNAs together with translation factors and other RNA-binding proteins (RBPs) in SGs ensures cell survival during stress and enables rapid SG disassembly and translation re-initiation upon recovery from stress. Importantly, impaired SG disassembly is linked to some neurodegenerative diseases, including amyotrophic lateral sclerosis and frontotemporal dementia. It is well established that in response to proteotoxic stress the UPS functions as a major PQC system by removing misfolded proteins. Accordingly, ubiquitylation is strongly induced in response to heat or oxidative stress. However, the specific subset of proteins undergoing ubiquitylation in response to distinct stimuli has remained largely elusive. Further, the contribution of ubiquitylation to stress resilience beyond the disposal of misfolded proteins is not well understood. In particular, the role of ubiquitylation in the dynamics of SG has remained controversial. 3 In the canonical ubiquitylation pathway ubiquitin is covalently conjugated to lysine (K) residues of target proteins by an enzymatic cascade, comprised of E1-activating enzymes, E2-conjugating enzymes, and E3 ligases. Ubiquitylation can form different types of lysine-linked polymeric chains that trigger distinct downstream processes. Proteins marked with K48-chains are typically targeted to the proteasome for proteolytic degradation, whereas other chain-types mediate proteasome-independent nonproteolytic signaling functions, as exemplified by K63-linked chains that mediate …
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影响因子：
8.8
作者：
Markmiller, Sebastian;Fulzele, Amit;Bennett, Eric J.
通讯作者：
Bennett, Eric J.
影响因子：
4.4
作者：
Tolay N;Buchberger A
通讯作者：
Buchberger A
影响因子：
16
作者：
Keiten-Schmitz, Jan;Wagner, Kristina;Mueller, Stefan
通讯作者：
Mueller, Stefan
DOI：
10.1126/science.abf6548
发表时间：
2021-06-25
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Gwon Y;Maxwell BA;Kolaitis RM;Zhang P;Kim HJ;Taylor JP
通讯作者：
Taylor JP
DOI：
10.1126/science.abc3593
发表时间：
2021-06-25
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Maxwell BA;Gwon Y;Mishra A;Peng J;Nakamura H;Zhang K;Kim HJ;Taylor JP
通讯作者：
Taylor JP