TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis

Ji An Pan; Yu Sun; Ya Ping Jiang; Alex J. Bott; Nadia Jaber; Zhixun Dou; Bin Yang; Juei Suei Chen; Joseph M. Catanzaro; Chunying Du; Wen Xing Ding; Maria T. Diaz-Meco; Jorge Moscat; Keiko Ozato; Richard Z. Lin; Wei Xing Zong

doi:10.1016/j.molcel.2016.02.007

TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis

Ji An Pan
, Yu Sun
, Ya Ping Jiang
, Alex J. Bott
, Nadia Jaber
, Zhixun Dou
, Bin Yang
, Juei Suei Chen
, Joseph M. Catanzaro
, Chunying Du
, Wen Xing Ding
, Maria T. Diaz-Meco
, Jorge Moscat
, Keiko Ozato
, Richard Z. Lin
, Wei Xing Zong

Physiology and Biophysics

Stony Brook University

Rutgers - The State University of New Jersey, New Brunswick
Stony Brook University
Tianjin Third Central Hospital
University of Cincinnati
University of Kansas
Sanford Burnham Prebys Medical Discovery Institute
National Institutes of Health

Research output: Contribution to journal › Article › peer-review

200 Scopus citations

Abstract

TRIM21 is a RING finger domain-containing ubiquitin E3 ligase whose expression is elevated in autoimmune disease. While TRIM21 plays an important role in immune activation during pathogen infection, little is known about its inherent cellular function. Here we show that TRIM21 plays an essential role in redox regulation by directly interacting with SQSTM1/p62 and ubiquitylating p62 at lysine 7 (K7) via K63-linkage. As p62 oligomerizes and sequesters client proteins in inclusions, the TRIM21-mediated p62 ubiquitylation abrogates p62 oligomerization and sequestration of proteins including Keap1, a negative regulator of antioxidant response. TRIM21-deficient cells display an enhanced antioxidant response and reduced cell death in response to oxidative stress. Genetic ablation of TRIM21 in mice confers protection from oxidative damages caused by arsenic-induced liver insult and pressure overload heart injury. Therefore, TRIM21 plays an essential role in p62-regulated redox homeostasis and may be a viable target for treating pathological conditions resulting from oxidative damage.

Original language	English
Pages (from-to)	720-733
Number of pages	14
Journal	Molecular Cell
Volume	61
Issue number	5
DOIs	https://doi.org/10.1016/j.molcel.2016.02.007
State	Published - Mar 3 2016

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Pan, J. A., Sun, Y., Jiang, Y. P., Bott, A. J., Jaber, N., Dou, Z., Yang, B., Chen, J. S., Catanzaro, J. M., Du, C., Ding, W. X., Diaz-Meco, M. T., Moscat, J., Ozato, K., Lin, R. Z., & Zong, W. X. (2016). TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis. Molecular Cell, 61(5), 720-733. https://doi.org/10.1016/j.molcel.2016.02.007

@article{d9b72a4c4d2047ba89e3cffc73c8842d,

title = "TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis",

abstract = "TRIM21 is a RING finger domain-containing ubiquitin E3 ligase whose expression is elevated in autoimmune disease. While TRIM21 plays an important role in immune activation during pathogen infection, little is known about its inherent cellular function. Here we show that TRIM21 plays an essential role in redox regulation by directly interacting with SQSTM1/p62 and ubiquitylating p62 at lysine 7 (K7) via K63-linkage. As p62 oligomerizes and sequesters client proteins in inclusions, the TRIM21-mediated p62 ubiquitylation abrogates p62 oligomerization and sequestration of proteins including Keap1, a negative regulator of antioxidant response. TRIM21-deficient cells display an enhanced antioxidant response and reduced cell death in response to oxidative stress. Genetic ablation of TRIM21 in mice confers protection from oxidative damages caused by arsenic-induced liver insult and pressure overload heart injury. Therefore, TRIM21 plays an essential role in p62-regulated redox homeostasis and may be a viable target for treating pathological conditions resulting from oxidative damage.",

author = "Pan, \{Ji An\} and Yu Sun and Jiang, \{Ya Ping\} and Bott, \{Alex J.\} and Nadia Jaber and Zhixun Dou and Bin Yang and Chen, \{Juei Suei\} and Catanzaro, \{Joseph M.\} and Chunying Du and Ding, \{Wen Xing\} and Diaz-Meco, \{Maria T.\} and Jorge Moscat and Keiko Ozato and Lin, \{Richard Z.\} and Zong, \{Wei Xing\}",

note = "Publisher Copyright: {\textcopyright} 2016 Elsevier Inc.",

year = "2016",

month = mar,

day = "3",

doi = "10.1016/j.molcel.2016.02.007",

language = "English",

volume = "61",

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journal = "Molecular Cell",

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T1 - TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis

AU - Pan, Ji An

AU - Sun, Yu

AU - Jiang, Ya Ping

AU - Bott, Alex J.

AU - Jaber, Nadia

AU - Dou, Zhixun

AU - Yang, Bin

AU - Chen, Juei Suei

AU - Catanzaro, Joseph M.

AU - Du, Chunying

AU - Ding, Wen Xing

AU - Diaz-Meco, Maria T.

AU - Moscat, Jorge

AU - Ozato, Keiko

AU - Lin, Richard Z.

AU - Zong, Wei Xing

PY - 2016/3/3

Y1 - 2016/3/3

N2 - TRIM21 is a RING finger domain-containing ubiquitin E3 ligase whose expression is elevated in autoimmune disease. While TRIM21 plays an important role in immune activation during pathogen infection, little is known about its inherent cellular function. Here we show that TRIM21 plays an essential role in redox regulation by directly interacting with SQSTM1/p62 and ubiquitylating p62 at lysine 7 (K7) via K63-linkage. As p62 oligomerizes and sequesters client proteins in inclusions, the TRIM21-mediated p62 ubiquitylation abrogates p62 oligomerization and sequestration of proteins including Keap1, a negative regulator of antioxidant response. TRIM21-deficient cells display an enhanced antioxidant response and reduced cell death in response to oxidative stress. Genetic ablation of TRIM21 in mice confers protection from oxidative damages caused by arsenic-induced liver insult and pressure overload heart injury. Therefore, TRIM21 plays an essential role in p62-regulated redox homeostasis and may be a viable target for treating pathological conditions resulting from oxidative damage.

AB - TRIM21 is a RING finger domain-containing ubiquitin E3 ligase whose expression is elevated in autoimmune disease. While TRIM21 plays an important role in immune activation during pathogen infection, little is known about its inherent cellular function. Here we show that TRIM21 plays an essential role in redox regulation by directly interacting with SQSTM1/p62 and ubiquitylating p62 at lysine 7 (K7) via K63-linkage. As p62 oligomerizes and sequesters client proteins in inclusions, the TRIM21-mediated p62 ubiquitylation abrogates p62 oligomerization and sequestration of proteins including Keap1, a negative regulator of antioxidant response. TRIM21-deficient cells display an enhanced antioxidant response and reduced cell death in response to oxidative stress. Genetic ablation of TRIM21 in mice confers protection from oxidative damages caused by arsenic-induced liver insult and pressure overload heart injury. Therefore, TRIM21 plays an essential role in p62-regulated redox homeostasis and may be a viable target for treating pathological conditions resulting from oxidative damage.

UR - https://www.scopus.com/pages/publications/84959490134

U2 - 10.1016/j.molcel.2016.02.007

DO - 10.1016/j.molcel.2016.02.007

M3 - Article

C2 - 26942676

SN - 1097-2765

VL - 61

SP - 720

EP - 733

JO - Molecular Cell

JF - Molecular Cell

IS - 5

ER -

TRIM21 Ubiquitylates SQSTM1/p62 and Suppresses Protein Sequestration to Regulate Redox Homeostasis

Abstract

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