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 (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.

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