TRIM16 controls assembly and degradation of protein aggregates by modulating the p62-NRF2 axis and autophagy.

Kautilya Kumar Jena,Pradyumna Kumar Sahoo,Subhash Mehto,Santosh Chauhan,Abdul Ahad,Shantibhusan Senapati,Sunil K Raghav,Gulam Hussain Syed,Parej Nath,Swati Chauhan,Srinivasa Prasad Kolapalli,Biswajit Das

doi:10.15252/embj.201798358

Kautilya Kumar Jena, Pradyumna Kumar Sahoo + Show 10 more

Open Access

https://doi.org/10.15252/embj.201798358

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Abstract

Sequestration of protein aggregates in inclusion bodies and their subsequent degradation prevents proteostasis imbalance, cytotoxicity, and proteinopathies. The underlying molecular mechanisms controlling the turnover of protein aggregates are mostly uncharacterized. Herein, we show that a TRIM family protein, TRIM16, governs the process of stress‐induced biogenesis and degradation of protein aggregates. TRIM16 facilitates protein aggregate formation by positively regulating the p62‐NRF2 axis. We show that TRIM16 is an integral part of the p62‐KEAP1‐NRF2 complex and utilizes multiple mechanisms for stabilizing NRF2. Under oxidative and proteotoxic stress conditions, TRIM16 activates ubiquitin pathway genes and p62 via NRF2, leading to ubiquitination of misfolded proteins and formation of protein aggregates. We further show that TRIM16 acts as a scaffold protein and, by interacting with p62, ULK1, ATG16L1, and LC3B, facilitates autophagic degradation of protein aggregates. Thus, TRIM16 streamlines the process of stress‐induced aggregate clearance and protects cells against oxidative/proteotoxic stress‐induced toxicity in vitro and in vivo. Taken together, this work identifies a new mechanism of protein aggregate turnover, which could be relevant in protein aggregation‐associated diseases such as neurodegeneration.

Highlights

Sequestration of protein aggregates in inclusion bodies and their subsequent degradation prevents proteostasis imbalance, cytotoxicity, and proteinopathies
Given the role of Tripartite motif (TRIM) proteins including TRIM16 in selective autophagy (Mandell et al, 2014a,b, 2016; Kimura et al, 2015, 2016a,b, 2017a,b; Chauhan et al, 2016; Fraiberg & Elazar, 2016; Kumar et al, 2017), we envisaged the role of TRIM16 in autophagic degradation of protein aggregates formed during oxidative or proteotoxic stress conditions
If TRIM16 mediates the degradation of ubiquitinated protein aggregates, ubiquitin dots should accumulate in TRIM16-depleted cells

Summary

Introduction

Sequestration of protein aggregates in inclusion bodies and their subsequent degradation prevents proteostasis imbalance, cytotoxicity, and proteinopathies. The underlying molecular mechanisms controlling the turnover of protein aggregates are mostly uncharacterized. We show that a TRIM family protein, TRIM16, governs the process of stress-induced biogenesis and degradation of protein aggregates. TRIM16 facilitates protein aggregate formation by positively regulating the p62-NRF2 axis. Under oxidative and proteotoxic stress conditions, TRIM16 activates ubiquitin pathway genes and p62 via NRF2, leading to ubiquitination of misfolded proteins and formation of protein aggregates. We further show that TRIM16 acts as a scaffold protein and, by interacting with p62, ULK1, ATG16L1, and LC3B, facilitates autophagic degradation of protein aggregates. TRIM16 streamlines the process of stress-induced aggregate clearance and protects cells against oxidative/proteotoxic stress-induced toxicity in vitro and in vivo. This work identifies a new mechanism of protein aggregate turnover, which could be relevant in protein aggregation-associated diseases such as neurodegeneration

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