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Nascent RHOH acts as a molecular brake on actomyosin-mediated effector functions of inflammatory neutrophils

In contrast to molecular changes associated with increased inflammatory responses, little is known about intracellular counter-regulatory mechanisms that control signaling cascades associated with functional responses of neutrophils. Active RHO GTPases are typically considered as effector proteins t...

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Autores principales: Peng, Shuang, Stojkov, Darko, Gao, Jian, Oberson, Kevin, Latzin, Philipp, Casaulta, Carmen, Yousefi, Shida, Simon, Hans-Uwe
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9514642/
https://www.ncbi.nlm.nih.gov/pubmed/36108062
http://dx.doi.org/10.1371/journal.pbio.3001794
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author Peng, Shuang
Stojkov, Darko
Gao, Jian
Oberson, Kevin
Latzin, Philipp
Casaulta, Carmen
Yousefi, Shida
Simon, Hans-Uwe
author_facet Peng, Shuang
Stojkov, Darko
Gao, Jian
Oberson, Kevin
Latzin, Philipp
Casaulta, Carmen
Yousefi, Shida
Simon, Hans-Uwe
author_sort Peng, Shuang
collection PubMed
description In contrast to molecular changes associated with increased inflammatory responses, little is known about intracellular counter-regulatory mechanisms that control signaling cascades associated with functional responses of neutrophils. Active RHO GTPases are typically considered as effector proteins that elicit cellular responses. Strikingly, we show here that RHOH, although being constitutively GTP-bound, limits neutrophil degranulation and the formation of neutrophil extracellular traps (NETs). Mechanistically, RHOH is induced under inflammatory conditions and binds to non-muscle myosin heavy chain IIA (NMHC IIA) in activated neutrophils in order to inhibit the transport of mitochondria and granules along actin filaments, which is partially reverted upon disruption of the interaction with NMHC IIA by introducing a mutation in RhoH at lysine 34 (RhoH(K34A)). In parallel, RHOH inhibits actin polymerization presumably by modulating RAC1 activity. In vivo studies using Rhoh(-/-) mice, demonstrate an increased antibacterial defense capability against Escherichia coli (E. coli). Collectively, our data reveal a previously undefined role of RHOH as a molecular brake for actomyosin-mediated neutrophil effector functions, which represents an intracellular regulatory axis involved in controlling the strength of an antibacterial inflammatory response.
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spelling pubmed-95146422022-09-28 Nascent RHOH acts as a molecular brake on actomyosin-mediated effector functions of inflammatory neutrophils Peng, Shuang Stojkov, Darko Gao, Jian Oberson, Kevin Latzin, Philipp Casaulta, Carmen Yousefi, Shida Simon, Hans-Uwe PLoS Biol Research Article In contrast to molecular changes associated with increased inflammatory responses, little is known about intracellular counter-regulatory mechanisms that control signaling cascades associated with functional responses of neutrophils. Active RHO GTPases are typically considered as effector proteins that elicit cellular responses. Strikingly, we show here that RHOH, although being constitutively GTP-bound, limits neutrophil degranulation and the formation of neutrophil extracellular traps (NETs). Mechanistically, RHOH is induced under inflammatory conditions and binds to non-muscle myosin heavy chain IIA (NMHC IIA) in activated neutrophils in order to inhibit the transport of mitochondria and granules along actin filaments, which is partially reverted upon disruption of the interaction with NMHC IIA by introducing a mutation in RhoH at lysine 34 (RhoH(K34A)). In parallel, RHOH inhibits actin polymerization presumably by modulating RAC1 activity. In vivo studies using Rhoh(-/-) mice, demonstrate an increased antibacterial defense capability against Escherichia coli (E. coli). Collectively, our data reveal a previously undefined role of RHOH as a molecular brake for actomyosin-mediated neutrophil effector functions, which represents an intracellular regulatory axis involved in controlling the strength of an antibacterial inflammatory response. Public Library of Science 2022-09-15 /pmc/articles/PMC9514642/ /pubmed/36108062 http://dx.doi.org/10.1371/journal.pbio.3001794 Text en © 2022 Peng et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Peng, Shuang
Stojkov, Darko
Gao, Jian
Oberson, Kevin
Latzin, Philipp
Casaulta, Carmen
Yousefi, Shida
Simon, Hans-Uwe
Nascent RHOH acts as a molecular brake on actomyosin-mediated effector functions of inflammatory neutrophils
title Nascent RHOH acts as a molecular brake on actomyosin-mediated effector functions of inflammatory neutrophils
title_full Nascent RHOH acts as a molecular brake on actomyosin-mediated effector functions of inflammatory neutrophils
title_fullStr Nascent RHOH acts as a molecular brake on actomyosin-mediated effector functions of inflammatory neutrophils
title_full_unstemmed Nascent RHOH acts as a molecular brake on actomyosin-mediated effector functions of inflammatory neutrophils
title_short Nascent RHOH acts as a molecular brake on actomyosin-mediated effector functions of inflammatory neutrophils
title_sort nascent rhoh acts as a molecular brake on actomyosin-mediated effector functions of inflammatory neutrophils
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9514642/
https://www.ncbi.nlm.nih.gov/pubmed/36108062
http://dx.doi.org/10.1371/journal.pbio.3001794
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