Peng, Shuang; Stojkov, Darko; Gao, Jian; Oberson, Kevin; Latzin, Philipp; Casaulta, Carmen; Yousefi, Shida; Simon, Hans-Uwe (2022). Nascent RHOH acts as a molecular brake on actomyosin-mediated effector functions of inflammatory neutrophils. PLoS biology, 20(9), e3001794. Public Library of Science 10.1371/journal.pbio.3001794
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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 (RhoHK34A). 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.
Item Type: |
Journal Article (Original Article) |
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Division/Institute: |
04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine 04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Pharmacology 04 Faculty of Medicine > Department of Gynaecology, Paediatrics and Endocrinology (DFKE) > Clinic of Paediatric Medicine > Paediatric Pneumology 09 Interdisciplinary Units > Microscopy Imaging Center (MIC) |
UniBE Contributor: |
Peng, Shuang, Stojkov, Darko, Oberson, Kevin, Latzin, Philipp, Casaulta, Carmen, Yousefi, Shida, Simon, Hans-Uwe |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
1544-9173 |
Publisher: |
Public Library of Science |
Language: |
English |
Submitter: |
Anette van Dorland |
Date Deposited: |
21 Sep 2022 14:55 |
Last Modified: |
06 Jan 2023 11:02 |
Publisher DOI: |
10.1371/journal.pbio.3001794 |
PubMed ID: |
36108062 |
BORIS DOI: |
10.48350/173048 |
URI: |
https://boris.unibe.ch/id/eprint/173048 |
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