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应激颗粒生命周期图

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40S STRESS GRANULE SEED NON-CANONICAL PREINITIATION COMPLEX STEP 1 Initiation of Cellular Stress STEP 2 Stress Granule (SG) Seed Formation STEP 4 Stress Granule Disassembly STEP 5 Resumption of Translation Increased local seedconcentration and weak low affinity interactions between seeds results in the coalescence of stress granules. UBAP2L is required for SG assembly, and controls the recruitment of SG component mRNPs, RBPs, and ribosomal subunits. -Heat stress-Arsenite exposure -Oxidative stress-Viral infection-UV irradiation G3BP1/2 and Caprin1 proteins complex and relocate to SG, regulating SG formation. Translating ribosomes run off, inhibiting translation and exposing the mRNA and 40S subunit interface. G3BP1/2, TIA1 , and FMRP help recruit and partition mRNA and mRNP into SG. YTHDF1/3 bind m6A- modified mRNA and accumulate around G3BP1/2 clusters to facilitate SG coalescence. hnRNP A1 is hyperphosphorylated and accumulates in the cytoplasm, incorporating into SGs. Disease-linked RBPs translocate from the nucleus and are recruited to SGs through secondary nucleation. – TDP43 strongly interacts with G3BP1 – FUS translocates in response togenomic stress Localized increase of G3BP1/2 and TIA1/R coupled with post-translationalmodifications leads tooligomerization. Recruitment of canonicalnucleating RNA-bindingproteins (RBPs) Several types of acutebiotic and abioticstresses can induceSG formation. Translation and protein production resumes. Preinitiation complexes re-form, recruiting eIF proteins and preparing for translation. YTHDF2 binds m6A- modified mRNA and colocalizes with G3BP1/2 in SGs. STEP 3 Stress Granule Formation STRESSGRANULE NUCLEUS G3BP1/2 TIA1/R CYTOPLASM rev. 2/22/23 Autophagic proteins facilitate disassembly, during which VCP helps separate proteins and SQSTM1 promotes translocation to autophagic vesicles. mRNA m7-G cap PolyA tail Start codon 40S ribosome Ataxin-2 Caprin1 FUS G3BP1/2 hnRNP A1 PABP1 TIA1/TIAR TDP43 UBAP2L YTHDF1/3 YTHDF2 AUG TIA1/R 40S G3BP1/2 TIA1/R TIA1/R G3BP1/2 eIF5 eIF4B eIF1A eIF4G eIF4A eIF1 eIF2 40S Key – Phosphorylation of eIF2α by PKR, PERK, GCN2, or HRI – mTOR regulates eIF4F; inactivation of mTOR drives eIF4F interference Stress granule formation is driven by liquid-liquid phase separation (LLPS). Size, shape, and structure of granules are influenced by seed characteristics, such as: – Seed composition – Concentration of RBPs/transcripts – Steric hindrance – Electrostatic interactions – Laplace pressures SG formation inhibits translation, and protects mRNA from degradation. When cellular stress ceases, ternary complexes are recruited and SGs disassemble.

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应激颗粒 (SG) 响应于急性生物应激与非生物应激形成。应激源包括但不限于毒性暴露、氧化应激、病毒感染、营养耗竭和辐射。1 细胞通过中断正常的蛋白质翻译过程应对这些应激源。通常，起始前复合体 (PIC) 因蛋白激酶 R (PKR)、蛋白激酶 RNA 样 ER 激酶 (PERK)、一般控制非阻遏蛋白 2 (GCN2) 或血红素调节抑制因子 (HRI) 使 eIF2α 磷酸化而受到抑制。1 此外，mTOR 失活导致 eIF4 结合蛋白活性升高，从而干扰 eIF4 翻译复合体组装。2 翻译核糖体随后脱落，暴露信使 RNA (mRNA) 和 40S 亚基，形成非经典 PIC。经典的成核 RNA 结合蛋白 (RBP)（包括 T 细胞限制性胞内抗原 1/TIA-1 相关蛋白 (TIA-1/R) 和 G3BP 应激颗粒组装因子 1/2 (G3BP1/2)）被募集到 PIC，不过其他成核蛋白也可以发挥这个作用。这个召集过程，联合 RNA 转录后修饰和成核蛋白翻译后修饰，促进“SG 核心”或“SG 种子”形成。该 SG 种子假设相对稳定，并且可以与其他 SG 种子寡聚体化形成更大的 SG 灶。

SG 形成过程主要受液-液相分离 (LLPS) 驱动，3 因此，SG 的大小、形状和结构受到众多的种子特征影响。SG LLPS 受种子组成强烈影响，这可能包括极其多样类别的 RNA 和 RBP、接头蛋白/支架蛋白和酶。4 诱导 SG 形成的应激类型也影响组成，1 RNA 转录后修饰和 RBP 的翻译后修饰也影响组成。鉴于 SG 组成高度可变，诸如空间位阻、静电相互作用和拉普拉斯压力等因素对 SG 大小和形状有着额外的重要影响；局部种子浓度升高和各种子之间微弱低亲和力相互作用驱动种子聚结。

已经鉴定许多对 SG 召集、组装和调节至关重要的关键蛋白质。细胞质多聚腺苷酸结合蛋白 1 (PABP1) 作为 mRNA 稳定性和翻译起始的关键调节分子，是 SG 的主要成分；它早期被募集，并且经常动态性活跃，穿梭出入 SG。5 同样，Ataxin-2 (ATXN2) 也促进 mRNA 的稳定性和翻译，并且是 SG 的核心组分。6 泛素相关蛋白样因子 2 (UBAP2L) 为 SG 组装所必需并且在某些条件下作用于 G3BP1 的上游。它还负责募集组分信使核糖核蛋白体 (mRNP)、RBP 和核糖体亚基。7 UBAP2L 下游的效应分子，例如 TIA1 和脆性 X 智力低下蛋白 (FMRP) 及其相关蛋白 FMR1 相互作用蛋白 2 (NUFIP2)，也定位至和/或辅助募集 mRNA 和 mRNP 至 SG。8,9 RNA 结合蛋白基序 3 (RBM3) 作为一种抗凋亡蛋白，也促进 SG 形成，10 而 DEAD 框肽 1 (DDX1) 结合 RNA 并在不同的应激条件下移位至 SG。11 有趣的是，在响应 eIF2α/4A 抑制时，G3BP1/2 是 SG 形成所必需的，但在热应激或渗透压应激中则非必需。G3BP1/2 和 Caprin1 蛋白形成复合体，Caprin 促进 G3BP1/2 LLPS。3 除了 Caprin1，USP10 还结合 G3BP1/2，这种结合与 Caprin-G3BP1/2 复合过程互斥；USP10 结合过程抑制 SG 形成，而 Caprin 结合过程促进 SG 形成。12 YTHDF1/2/3 结合 m6A 修饰的 mRNA。YTHDF1/3 在 G3BP1/2 簇周围积累，而 YTHDF2 与 G3BP1/2 在 SG 内部共定位，从而进一步促进 SG 形成。13

疾病相关 RBP 从胞核移位，以便经二次成核召集入 SG。这些蛋白包括 TAR DNA 结合蛋白 43 (TDP43) 和 FET 家族的 RBP，其中 TDP43 通过与 G3BP1/2 的强相互作用调控 SG 的形成，14 FET 家族包括 FUS/TLS、EWS 和 TAF15。15 面对基因组应激时，FUS RNA 结合蛋白 (FUS) 和 TATA 框结合蛋白相关因子 15 (TAF15) 会转运至 SG。15,16 异质核核糖核蛋白 A1 (hnRNP A1) 在过度磷酸化时会发生转运和纤维化，从而驱动 LLPS 形成富含蛋白质的液滴，进而参与 SG 的形成。17

一旦细胞应激停止，则召集三元复合体驱动 SG 解散。自噬蛋白通过粒噬促进解散，由此自噬小泡封裹并分解 SG。DDX1 可以帮助促进这个过程，尽管其对此并非必需。11 隔离体 1 (SQSTM1) 促进 SG 移位至自噬囊泡。18,19 ATP 酶含缬酪肽蛋白 (VCP) 因 unc-51 样自噬激活激酶 1/2 (ULK1/2) 的磷酸化而激活，进而促进 SG 的颗粒自噬。20 PIC 重新形成，eIF 蛋白被募集，当翻译复合体完全重组后，翻译过程恢复。

主要文献：

  1. Panas, M. D., Ivanov, P. & Anderson, P. Mechanistic insights into mammalian stress granule dynamics. Journal of Cell Biology. 2016; 215:313–323
  2. Sonenberg, N. & Hinnebusch, A. G. Regulation of Translation Initiation in Eukaryotes: Mechanisms and Biological Targets. Cell. 2009;136:731–745
  3. Li, J., Zhang, Y., Chen, X., et al. Protein phase separation and its role in chromatin organization and diseases. Biomedicine & Pharmacotherapy. 2021;138:111520
  4. Jain, S., Wheeler, J. R., Walters, R. W., et al. ATPase-Modulated Stress Granules Contain a Diverse Proteome and Substructure. Cell. 2016;164:487–98
  5. Kedersha, N., Cho, M. R., Li, W., et al. Dynamic shuttling of TIA-1 accompanies the recruitment of mRNA to mammalian stress granules. Journal of Cell Biology. 2000;151:1257–1268
  6. Nonhoff, U., Ralser, M., Welzel, F., et al. Ataxin-2 interacts with the DEAD/H-box RNA helicase DDX6 and interferes with P-bodies and stress granules. Mol Biol Cell. 2007;18:1385–1396
  7. Cirillo, L., Cieren, A., Barbieri, S.,et al. UBAP2L Forms Distinct Cores that Act in Nucleating Stress Granules Upstream of G3BP1. Curr Biol. 2020;30:698-707.e6
  8. Matheny, T., van Treeck, B., Huynh, T. N., et al. RNA partitioning into stress granules is based on the summation of multiple interactions. RNA. 2021;27:174–189
  9. Ozeki, K., Sugiyama, M., Akter, K. A.,et al. FAM98A is localized to stress granules and associates with multiple stress granule-localized proteins. Mol Cell Biochem. 2019; 451:107–115
  10. Si, W., Li, Z., Huang, Z., et al. RNA Binding Protein Motif 3 Inhibits Oxygen-Glucose Deprivation/Reoxygenation-Induced Apoptosis Through Promoting Stress Granules Formation in PC12 Cells and Rat Primary Cortical Neurons. Front Cell Neurosci. 2020;14:287
  11. Li, L., Garg, M., Wang, Y., et al. DEAD Box 1 (DDX1) protein binds to and protects cytoplasmic stress response mRNAs in cells exposed to oxidative stress. Journal of Biological Chemistry. 2022;298:102180
  12. Kedersha, N., Panas, M. D., Achorn, C. A., et al. G3BP-Caprin1-USP10 complexes mediate stress granule condensation and associate with 40S subunits. Journal of Cell Biology. 2016;212:845–860
  13. Fu, Y. & Zhuang, X. m6A-binding YTHDF proteins promote stress granule formation. Nat Chem Biol. 2020;16:955–963
  14. Besnard-Guérin, C. Cytoplasmic localization of amyotrophic lateral sclerosis-related TDP-43 proteins modulates stress granule formation. Eur J Neurosci. 2020;52:3995–4008
  15. Blechingberg, J., Luo, Y., Bolund, L.,et al. Gene Expression Responses to FUS, EWS, and TAF15 Reduction and Stress Granule Sequestration Analyses Identifies FET-Protein Non-Redundant Functions. PLoS One. 2012;7:e46251
  16. Sama, R. R. K., Ward, C. L., Kaushansky, L. J., et al. FUS/TLS assembles into stress granules and is a prosurvival factor during hyperosmolar stress. J Cell Physiol. 2013;228:2222–31
  17. Molliex, A., Temirov, J., Lee, J., et al. Phase Separation by Low Complexity Domains Promotes Stress Granule Assembly and Drives Pathological Fibrillization. Cell. 2015;163:123–133
  18. Chitiprolu, M., Jagow, C., Tremblay, V., et al. A complex of C9ORF72 and p62 uses arginine methylation to eliminate stress granules by autophagy. Nature Communications. 2018;9:1–18.
  19. Sun, D., Wu, R., Zheng, J., et al. Polyubiquitin chain-induced p62 phase separation drives autophagic cargo segregation. Cell Researc. 2018;28:405–415
  20. Wang, B., Maxwell, B. A., Joo, J. H.,et al. ULK1 and ULK2 Regulate Stress Granule Disassembly Through Phosphorylation and Activation of VCP/p97. Mol Cell. 2019;74:742-757.e8

创建于 2023 年 2 月

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