Serine ubiquitination of SQSTM1 regulates NFE2L2-dependent redox homeostasis.

IF 14.6 1区生物学 Q1 CELL BIOLOGY

Autophagy Pub Date : 2024-09-18 DOI:10.1080/15548627.2024.2404375

Rukmini Mukherjee,Anshu Bhattacharya,João Mello-Vieira,Santosh Kumar Kuncha,Marina Hoffmann,Alexis Gonzalez,Rajeshwari Rathore,Attinder Chadha,Donghyuk Shin,Thomas Colby,Ivan Matic,Shaeri Mukherjee,Mohit Misra,Ivan Dikic

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引用次数: 0

Abstract

The KEAP1-NFE2L2 axis is essential for the cellular response against metabolic and oxidative stress. KEAP1 is an adaptor protein of CUL3 (cullin 3) ubiquitin ligase that controls the cellular levels of NFE2L2, a critical transcription factor of several cytoprotective genes. Oxidative stress, defective autophagy and pathogenic infections activate NFE2L2 signaling through phosphorylation of the autophagy receptor protein SQSTM1, which competes with NFE2L2 for binding to KEAP1. Here we show that phosphoribosyl-linked serine ubiquitination of SQSTM1 catalyzed by SidE effectors of Legionella pneumophila controls NFE2L2 signaling and cell metabolism upon Legionella infection. Serine ubiquitination of SQSTM1 sterically blocks its binding to KEAP1, resulting in NFE2L2 ubiquitination and degradation. This reduces NFE2L2-dependent antioxidant synthesis in the early phase of infection. Levels of serine ubiquitinated SQSTM1 diminish in the later stage of infection allowing the expression of NFE2L2-target genes; causing a differential regulation of the host metabolome and proteome in a NFE2L2-dependent manner.

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SQSTM1 的丝氨酸泛素化调节 NFE2L2 依赖性氧化还原稳态。

KEAP1-NFE2L2 轴对于细胞应对代谢和氧化应激至关重要。KEAP1 是 CUL3（cullin 3）泛素连接酶的适配蛋白，它控制着 NFE2L2 的细胞水平，而 NFE2L2 是多个细胞保护基因的关键转录因子。氧化应激、自噬缺陷和病原体感染会通过自噬受体蛋白 SQSTM1 的磷酸化激活 NFE2L2 信号，而 SQSTM1 会与 NFE2L2 竞争与 KEAP1 的结合。在这里，我们发现在军团菌感染时，嗜肺军团菌的SidE效应因子会催化与磷酸核糖连接的丝氨酸泛素化SQSTM1，从而控制NFE2L2信号传导和细胞代谢。SQSTM1 的丝氨酸泛素化会阻止其与 KEAP1 的结合，从而导致 NFE2L2 泛素化和降解。这就减少了感染初期依赖 NFE2L2 的抗氧化剂合成。在感染后期，丝氨酸泛素化的 SQSTM1 水平会降低，从而使 NFE2L2 靶基因得以表达；从而以 NFE2L2 依赖性方式对宿主代谢组和蛋白质组进行不同的调节。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Autophagy 生物-细胞生物学

CiteScore

21.30

自引率

2.30%

发文量

277

审稿时长

1 months

期刊介绍： Autophagy is a peer-reviewed journal that publishes research on autophagic processes, including the lysosome/vacuole dependent degradation of intracellular material. It aims to be the premier journal in the field and covers various connections between autophagy and human health and disease, such as cancer, neurodegeneration, aging, diabetes, myopathies, and heart disease. Autophagy is interested in all experimental systems, from yeast to human. Suggestions for specialized topics are welcome. The journal accepts the following types of articles: Original research, Reviews, Technical papers, Brief Reports, Addenda, Letters to the Editor, Commentaries and Views, and Articles on science and art. Autophagy is abstracted/indexed in Adis International Ltd (Reactions Weekly), EBSCOhost (Biological Abstracts), Elsevier BV (EMBASE and Scopus), PubMed, Biological Abstracts, Science Citation Index Expanded, Web of Science, and MEDLINE.