Posttranslational Modification of HOIP Blocks Toll-Like Receptor 4-Mediated Linear-Ubiquitin-Chain Formation

ABSTRACT Linear ubiquitination is an atypical posttranslational modification catalyzed by the linear-ubiquitin-chain assembly complex (LUBAC), containing HOIP, HOIL-1L, and Sharpin. LUBAC facilitates NF-κB activation and inflammation upon receptor stimulation by ligating linear ubiquitin chains to c...

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Autores principales:	James Bowman, Mary A. Rodgers, Mude Shi, Rina Amatya, Bruce Hostager, Kazuhiro Iwai, Shou-Jiang Gao, Jae U. Jung
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Lenguaje:	EN
Publicado:	American Society for Microbiology 2015
Materias:	Microbiology QR1-502
Acceso en línea:	https://doaj.org/article/7b17e42dd58d43dbad7b1292f30f24fd
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spelling	oai:doaj.org-article:7b17e42dd58d43dbad7b1292f30f24fd2021-11-15T15:41:23ZPosttranslational Modification of HOIP Blocks Toll-Like Receptor 4-Mediated Linear-Ubiquitin-Chain Formation10.1128/mBio.01777-152150-7511https://doaj.org/article/7b17e42dd58d43dbad7b1292f30f24fd2015-12-01T00:00:00Zhttps://journals.asm.org/doi/10.1128/mBio.01777-15https://doaj.org/toc/2150-7511ABSTRACT Linear ubiquitination is an atypical posttranslational modification catalyzed by the linear-ubiquitin-chain assembly complex (LUBAC), containing HOIP, HOIL-1L, and Sharpin. LUBAC facilitates NF-κB activation and inflammation upon receptor stimulation by ligating linear ubiquitin chains to critical signaling molecules. Indeed, linear-ubiquitination-dependent signaling is essential to prevent pyogenic bacterial infections that can lead to death. While linear ubiquitination is essential for intracellular receptor signaling upon microbial infection, this response must be measured and stopped to avoid tissue damage and autoimmunity. While LUBAC is activated upon bacterial stimulation, the mechanisms regulating LUBAC activity in response to bacterial stimuli have remained elusive. We demonstrate that LUBAC activity itself is downregulated through ubiquitination, specifically, ubiquitination of the catalytic subunit HOIP at the carboxyl-terminal lysine 1056. Ubiquitination of Lys1056 dynamically altered HOIP conformation, resulting in the suppression of its catalytic activity. Consequently, HOIP Lys1056-to-Arg mutation led not only to persistent LUBAC activity but also to prolonged NF-κB activation induced by bacterial lipopolysaccharide-mediated Toll-like receptor 4 (TLR4) stimulation, whereas it showed no effect on NF-κB activation induced by CD40 stimulation. This study describes a novel posttranslational regulation of LUBAC-mediated linear ubiquitination that is critical for specifically directing TLR4-mediated NF-κB activation. IMPORTANCE Posttranslational modification of proteins enables cells to respond quickly to infections and immune stimuli in a tightly controlled manner. Specifically, covalent modification of proteins with the small protein ubiquitin is essential for cells to initiate and terminate immune signaling in response to bacterial and viral infection. This process is controlled by ubiquitin ligase enzymes, which themselves must be regulated to prevent persistent and deleterious immune signaling. However, how this regulation is achieved is poorly understood. This paper reports a novel ubiquitination event of the atypical ubiquitin ligase HOIP that is required to terminate bacterial lipopolysaccharide (LPS)-induced TLR4 immune signaling. Ubiquitination causes the HOIP ligase to undergo a conformational change, which blocks its enzymatic activity and ultimately terminates LPS-induced TLR4 signaling. These findings provide a new mechanism for controlling HOIP ligase activity that is vital to properly regulate a proinflammatory immune response.James BowmanMary A. RodgersMude ShiRina AmatyaBruce HostagerKazuhiro IwaiShou-Jiang GaoJae U. JungAmerican Society for MicrobiologyarticleMicrobiologyQR1-502ENmBio, Vol 6, Iss 6 (2015)
institution	DOAJ
collection	DOAJ
language	EN
topic	Microbiology QR1-502
spellingShingle	Microbiology QR1-502 James Bowman Mary A. Rodgers Mude Shi Rina Amatya Bruce Hostager Kazuhiro Iwai Shou-Jiang Gao Jae U. Jung Posttranslational Modification of HOIP Blocks Toll-Like Receptor 4-Mediated Linear-Ubiquitin-Chain Formation
description	ABSTRACT Linear ubiquitination is an atypical posttranslational modification catalyzed by the linear-ubiquitin-chain assembly complex (LUBAC), containing HOIP, HOIL-1L, and Sharpin. LUBAC facilitates NF-κB activation and inflammation upon receptor stimulation by ligating linear ubiquitin chains to critical signaling molecules. Indeed, linear-ubiquitination-dependent signaling is essential to prevent pyogenic bacterial infections that can lead to death. While linear ubiquitination is essential for intracellular receptor signaling upon microbial infection, this response must be measured and stopped to avoid tissue damage and autoimmunity. While LUBAC is activated upon bacterial stimulation, the mechanisms regulating LUBAC activity in response to bacterial stimuli have remained elusive. We demonstrate that LUBAC activity itself is downregulated through ubiquitination, specifically, ubiquitination of the catalytic subunit HOIP at the carboxyl-terminal lysine 1056. Ubiquitination of Lys1056 dynamically altered HOIP conformation, resulting in the suppression of its catalytic activity. Consequently, HOIP Lys1056-to-Arg mutation led not only to persistent LUBAC activity but also to prolonged NF-κB activation induced by bacterial lipopolysaccharide-mediated Toll-like receptor 4 (TLR4) stimulation, whereas it showed no effect on NF-κB activation induced by CD40 stimulation. This study describes a novel posttranslational regulation of LUBAC-mediated linear ubiquitination that is critical for specifically directing TLR4-mediated NF-κB activation. IMPORTANCE Posttranslational modification of proteins enables cells to respond quickly to infections and immune stimuli in a tightly controlled manner. Specifically, covalent modification of proteins with the small protein ubiquitin is essential for cells to initiate and terminate immune signaling in response to bacterial and viral infection. This process is controlled by ubiquitin ligase enzymes, which themselves must be regulated to prevent persistent and deleterious immune signaling. However, how this regulation is achieved is poorly understood. This paper reports a novel ubiquitination event of the atypical ubiquitin ligase HOIP that is required to terminate bacterial lipopolysaccharide (LPS)-induced TLR4 immune signaling. Ubiquitination causes the HOIP ligase to undergo a conformational change, which blocks its enzymatic activity and ultimately terminates LPS-induced TLR4 signaling. These findings provide a new mechanism for controlling HOIP ligase activity that is vital to properly regulate a proinflammatory immune response.
format	article
author	James Bowman Mary A. Rodgers Mude Shi Rina Amatya Bruce Hostager Kazuhiro Iwai Shou-Jiang Gao Jae U. Jung
author_facet	James Bowman Mary A. Rodgers Mude Shi Rina Amatya Bruce Hostager Kazuhiro Iwai Shou-Jiang Gao Jae U. Jung
author_sort	James Bowman
title	Posttranslational Modification of HOIP Blocks Toll-Like Receptor 4-Mediated Linear-Ubiquitin-Chain Formation
title_short	Posttranslational Modification of HOIP Blocks Toll-Like Receptor 4-Mediated Linear-Ubiquitin-Chain Formation
title_full	Posttranslational Modification of HOIP Blocks Toll-Like Receptor 4-Mediated Linear-Ubiquitin-Chain Formation
title_fullStr	Posttranslational Modification of HOIP Blocks Toll-Like Receptor 4-Mediated Linear-Ubiquitin-Chain Formation
title_full_unstemmed	Posttranslational Modification of HOIP Blocks Toll-Like Receptor 4-Mediated Linear-Ubiquitin-Chain Formation
title_sort	posttranslational modification of hoip blocks toll-like receptor 4-mediated linear-ubiquitin-chain formation
publisher	American Society for Microbiology
publishDate	2015
url	https://doaj.org/article/7b17e42dd58d43dbad7b1292f30f24fd
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Posttranslational Modification of HOIP Blocks Toll-Like Receptor 4-Mediated Linear-Ubiquitin-Chain Formation

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