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MALT1-Dependent Cleavage of HOIL1 Modulates Canonical NF-κB Signaling and Inflammatory Responsiveness

Nuclear factor kappa B (NF-κB) is a critical transcription factor involved in regulating cell activation, inflammation, and survival. The linear ubiquitin chain assembly complex (LUBAC) which consists of HOIL1, HOIP, and SHARPIN, catalyzes the linear ubiquitination of target proteins—a post-translat...

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Autores principales: Fung, Shan-Yu, Lu, Henry Y., Sharma, Mehul, Sharma, Ashish A., Saferali, Aabida, Jia, Alicia, Abraham, Libin, Klein, Theo, Gold, Michael R., Noterangelo, Luigi D., Overall, Christopher M., Turvey, Stuart E.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8552041/
https://www.ncbi.nlm.nih.gov/pubmed/34721419
http://dx.doi.org/10.3389/fimmu.2021.749794
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author Fung, Shan-Yu
Lu, Henry Y.
Sharma, Mehul
Sharma, Ashish A.
Saferali, Aabida
Jia, Alicia
Abraham, Libin
Klein, Theo
Gold, Michael R.
Noterangelo, Luigi D.
Overall, Christopher M.
Turvey, Stuart E.
author_facet Fung, Shan-Yu
Lu, Henry Y.
Sharma, Mehul
Sharma, Ashish A.
Saferali, Aabida
Jia, Alicia
Abraham, Libin
Klein, Theo
Gold, Michael R.
Noterangelo, Luigi D.
Overall, Christopher M.
Turvey, Stuart E.
author_sort Fung, Shan-Yu
collection PubMed
description Nuclear factor kappa B (NF-κB) is a critical transcription factor involved in regulating cell activation, inflammation, and survival. The linear ubiquitin chain assembly complex (LUBAC) which consists of HOIL1, HOIP, and SHARPIN, catalyzes the linear ubiquitination of target proteins—a post-translational modification that is essential for NF-κB activation. Human germline pathogenic variants that dysregulate linear ubiquitination and NF-κB signaling are associated with immunodeficiency and/or autoinflammation including dermatitis, recurrent fevers, systemic inflammation and enteropathy. We previously identified MALT1 paracaspase as a novel negative regulator of LUBAC by proteolytic cleavage of HOIL1. To directly investigate the impact of HOIL1 cleavage activity on the inflammatory response, we employed a stable transduction system to express and directly compare non-cleavable HOIL1 with wild-type HOIL1 in primary HOIL1-deficient patient skin fibroblasts. We discovered that non-cleavable HOIL1 resulted in enhanced NF-κB signaling in response to innate stimuli. Transcriptomics revealed enrichment of inflammation and proinflammatory cytokine-related pathways after stimulation. Multiplexed cytokine assays confirmed a ‘hyperinflammatory’ phenotype in these cells. This work highlights the physiological importance of MALT1-dependent cleavage and modulation of HOIL1 on NF-κB signaling and inflammation, provides a mechanism for the autoinflammation observed in MALT1-deficient patients, and will inform the development of therapeutics that target MALT1 paracaspase and LUBAC function in treating autoinflammatory skin diseases.
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spelling pubmed-85520412021-10-29 MALT1-Dependent Cleavage of HOIL1 Modulates Canonical NF-κB Signaling and Inflammatory Responsiveness Fung, Shan-Yu Lu, Henry Y. Sharma, Mehul Sharma, Ashish A. Saferali, Aabida Jia, Alicia Abraham, Libin Klein, Theo Gold, Michael R. Noterangelo, Luigi D. Overall, Christopher M. Turvey, Stuart E. Front Immunol Immunology Nuclear factor kappa B (NF-κB) is a critical transcription factor involved in regulating cell activation, inflammation, and survival. The linear ubiquitin chain assembly complex (LUBAC) which consists of HOIL1, HOIP, and SHARPIN, catalyzes the linear ubiquitination of target proteins—a post-translational modification that is essential for NF-κB activation. Human germline pathogenic variants that dysregulate linear ubiquitination and NF-κB signaling are associated with immunodeficiency and/or autoinflammation including dermatitis, recurrent fevers, systemic inflammation and enteropathy. We previously identified MALT1 paracaspase as a novel negative regulator of LUBAC by proteolytic cleavage of HOIL1. To directly investigate the impact of HOIL1 cleavage activity on the inflammatory response, we employed a stable transduction system to express and directly compare non-cleavable HOIL1 with wild-type HOIL1 in primary HOIL1-deficient patient skin fibroblasts. We discovered that non-cleavable HOIL1 resulted in enhanced NF-κB signaling in response to innate stimuli. Transcriptomics revealed enrichment of inflammation and proinflammatory cytokine-related pathways after stimulation. Multiplexed cytokine assays confirmed a ‘hyperinflammatory’ phenotype in these cells. This work highlights the physiological importance of MALT1-dependent cleavage and modulation of HOIL1 on NF-κB signaling and inflammation, provides a mechanism for the autoinflammation observed in MALT1-deficient patients, and will inform the development of therapeutics that target MALT1 paracaspase and LUBAC function in treating autoinflammatory skin diseases. Frontiers Media S.A. 2021-10-14 /pmc/articles/PMC8552041/ /pubmed/34721419 http://dx.doi.org/10.3389/fimmu.2021.749794 Text en Copyright © 2021 Fung, Lu, Sharma, Sharma, Saferali, Jia, Abraham, Klein, Gold, Noterangelo, Overall and Turvey https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Fung, Shan-Yu
Lu, Henry Y.
Sharma, Mehul
Sharma, Ashish A.
Saferali, Aabida
Jia, Alicia
Abraham, Libin
Klein, Theo
Gold, Michael R.
Noterangelo, Luigi D.
Overall, Christopher M.
Turvey, Stuart E.
MALT1-Dependent Cleavage of HOIL1 Modulates Canonical NF-κB Signaling and Inflammatory Responsiveness
title MALT1-Dependent Cleavage of HOIL1 Modulates Canonical NF-κB Signaling and Inflammatory Responsiveness
title_full MALT1-Dependent Cleavage of HOIL1 Modulates Canonical NF-κB Signaling and Inflammatory Responsiveness
title_fullStr MALT1-Dependent Cleavage of HOIL1 Modulates Canonical NF-κB Signaling and Inflammatory Responsiveness
title_full_unstemmed MALT1-Dependent Cleavage of HOIL1 Modulates Canonical NF-κB Signaling and Inflammatory Responsiveness
title_short MALT1-Dependent Cleavage of HOIL1 Modulates Canonical NF-κB Signaling and Inflammatory Responsiveness
title_sort malt1-dependent cleavage of hoil1 modulates canonical nf-κb signaling and inflammatory responsiveness
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8552041/
https://www.ncbi.nlm.nih.gov/pubmed/34721419
http://dx.doi.org/10.3389/fimmu.2021.749794
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