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TRIM22 通过介导 GABARAPs 和 PLEKHM1 的结合促进自噬体-溶酶体融合。

TRIM22 facilitates autophagosome-lysosome fusion by mediating the association of GABARAPs and PLEKHM1.

机构信息

Department of Biomedical Sciences, Ajou University School of Medicine, Suwon, Republic of Korea.

Department of Anatomy, College of Medicine, and Program in Biomedical Science & Engineering, Inha University, Incheon, Republic of Korea.

出版信息

Autophagy. 2024 May;20(5):1098-1113. doi: 10.1080/15548627.2023.2287925. Epub 2023 Dec 7.

DOI:10.1080/15548627.2023.2287925
PMID:38009729
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11135824/
Abstract

Tripartite motif (TRIM) proteins are a large family of E3 ubiquitin ligases implicated in antiviral defense systems, tumorigenesis, and protein quality control. TRIM proteins contribute to protein quality control by regulating the ubiquitin-proteasome system, endoplasmic reticulum-associated degradation, and macroautophagy/autophagy. However, the detailed mechanisms through which various TRIM proteins regulate downstream events have not yet been fully elucidated. Herein, we identified a novel function of TRIM22 in the regulation of autophagy. TRIM22 promotes autophagosome-lysosome fusion by mediating the association of GABARAP family proteins with PLEKHM1, thereby inducing the autophagic clearance of protein aggregates, independent of its E3 ubiquitin ligase activity. Furthermore, a TRIM22 variant associated with early-onset familial Alzheimer disease interferes with autophagosome-lysosome fusion and autophagic clearance. These findings suggest TRIM22 as a critical autophagic regulator that orchestrates autophagosome-lysosome fusion by scaffolding autophagy-related proteins, thus representing a potential therapeutic target in neurodegenerative diseases. AD: Alzheimer disease; ADAOO: AD age of onset; AICD: APP intracellular domain; APP: amyloid beta precursor protein; BSA: bovine serum albumin; cDNAs: complementary DNAs; CQ: chloroquine; CTF: carboxyl-terminal fragment; EBSS: Earle's balanced salt solution; GABARAP: GABA type A receptor-associated protein; GST: glutathione S-transferase; HA: hemagglutinin; HOPS: homotypic fusion and protein sorting; IFN: interferon; IL1A/IL-1α: interleukin 1 alpha; KO: knockout; MTORC1: mechanistic target of rapamycin kinase complex 1; NFKBIA/IκBα: NFKB inhibitor alpha; NFE2L2/NRF2: NFE2 like bZIP transcription factor; PBS: phosphate-buffered saline; PI3K: class I phosphoinositide 3-kinase; PLA: proximity ligation assay; PLEKHM1: pleckstrin homology and RUN domain containing M1; PSEN1: presenilin 1; SEM: standard errors of the means; SNAREs: soluble N-ethylmaleimide-sensitive factor attachment protein receptors; SNCA: synuclein alpha; SNP: single nucleotide polymorphism; TBS: tris-buffered saline; TNF/TNF-α: tumor necrosis factor; TRIM: tripartite motif; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type.

摘要

三结构域蛋白（TRIM）是一大类 E3 泛素连接酶，参与抗病毒防御系统、肿瘤发生和蛋白质质量控制。TRIM 蛋白通过调节泛素-蛋白酶体系统、内质网相关降解和巨自噬/自噬来促进蛋白质质量控制。然而，各种 TRIM 蛋白调节下游事件的详细机制尚未完全阐明。在此，我们鉴定了 TRIM22 在自噬调节中的新功能。TRIM22 通过介导 GABARAP 家族蛋白与 PLEKHM1 的结合，促进自噬体-溶酶体融合，从而诱导蛋白质聚集体的自噬清除，而不依赖其 E3 泛素连接酶活性。此外，与早发性家族性阿尔茨海默病相关的 TRIM22 变体干扰自噬体-溶酶体融合和自噬清除。这些发现表明 TRIM22 是一种关键的自噬调节剂，通过支架自噬相关蛋白来协调自噬体-溶酶体融合，因此代表神经退行性疾病的潜在治疗靶点。AD：阿尔茨海默病；ADAOO：阿尔茨海默病发病年龄；AICD：APP 细胞内结构域；APP：淀粉样前体蛋白；BSA：牛血清白蛋白；cDNAs：互补 DNA；CQ：氯喹；CTF：羧基末端片段；EBSS：Earle 的平衡盐溶液；GABARAP：GABA 型 A 受体相关蛋白；GST：谷胱甘肽 S-转移酶；HA：血凝素；HOPS：同源融合和蛋白质分选；IFN：干扰素；IL1A/IL-1α：白细胞介素 1α；KO：敲除；MTORC1：雷帕霉素激酶复合物 1；NFKBIA/IκBα：NFKB 抑制剂 alpha；NFE2L2/NRF2：NFE2 样 bZIP 转录因子；PBS：磷酸盐缓冲盐水；PI3K：I 类磷酸肌醇 3-激酶；PLA：邻近连接分析；PLEKHM1：pleckstrin 同源和 RUN 域包含 M1；PSEN1：早老素 1；SEM：均值的标准误差；SNAREs：可溶性 N-乙基马来酰亚胺敏感因子附着蛋白受体；SNCA：突触核蛋白 alpha；SNP：单核苷酸多态性；TBS：三缓冲盐水；TNF/TNF-α：肿瘤坏死因子；TRIM：三结构域；ULK1：UNC-51 样自噬激活激酶 1；WT：野生型。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8baf/11135824/476b34afbea4/KAUP_A_2287925_F0008_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8baf/11135824/b689c5b23d3c/KAUP_A_2287925_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8baf/11135824/87f3c73b3b70/KAUP_A_2287925_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8baf/11135824/7e4f1a0888fb/KAUP_A_2287925_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8baf/11135824/c02cbaab333e/KAUP_A_2287925_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8baf/11135824/e417cf7460f3/KAUP_A_2287925_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8baf/11135824/cdc22adbaa2b/KAUP_A_2287925_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8baf/11135824/3b27de538a70/KAUP_A_2287925_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8baf/11135824/476b34afbea4/KAUP_A_2287925_F0008_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8baf/11135824/b689c5b23d3c/KAUP_A_2287925_F0001_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8baf/11135824/87f3c73b3b70/KAUP_A_2287925_F0002_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8baf/11135824/7e4f1a0888fb/KAUP_A_2287925_F0003_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8baf/11135824/c02cbaab333e/KAUP_A_2287925_F0004_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8baf/11135824/e417cf7460f3/KAUP_A_2287925_F0005_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8baf/11135824/cdc22adbaa2b/KAUP_A_2287925_F0006_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8baf/11135824/3b27de538a70/KAUP_A_2287925_F0007_C.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8baf/11135824/476b34afbea4/KAUP_A_2287925_F0008_C.jpg

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本文引用的文献

[1]
TRIM22 actives PI3K/Akt/mTOR pathway to promote psoriasis through enhancing cell proliferation and inflammation and inhibiting autophagy.

Cutan Ocul Toxicol. 2022-12

[2]
TRIM22 inhibits osteosarcoma progression through destabilizing NRF2 and thus activation of ROS/AMPK/mTOR/autophagy signaling.

Redox Biol. 2022-7

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Loss of TAX1BP1-Directed Autophagy Results in Protein Aggregate Accumulation in the Brain.

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