新生的 RHOH 对肌动球蛋白介导的炎性中性粒细胞效应功能起到分子制动的作用。,PLOS Biology

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新生的 RHOH 对肌动球蛋白介导的炎性中性粒细胞效应功能起到分子制动的作用。
PLOS Biology ( IF 7.8 ) Pub Date : 2022-09-15 , DOI: 10.1371/journal.pbio.3001794
Shuang Peng ₁ , Darko Stojkov ₁ , Jian Gao ₂ , Kevin Oberson ₁ , Philipp Latzin ₃ , Carmen Casaulta ₃ , Shida Yousefi ₁ , Hans-Uwe Simon _{1,

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Affiliation

与与炎症反应增加相关的分子变化相反，对控制与中性粒细胞功能反应相关的信号级联的细胞内反调节机制知之甚少。活性 RHO GTP 酶通常被认为是引发细胞反应的效应蛋白。引人注目的是，我们在这里展示了 RHOH，虽然是组成性 GTP 结合的，但限制了中性粒细胞脱粒和中性粒细胞胞外陷阱 (NET) 的形成。从机制上讲，RHOH 在炎症条件下被诱导并与活化的中性粒细胞中的非肌肉肌球蛋白重链 IIA (NMHC IIA) 结合，以抑制线粒体和颗粒沿肌动蛋白丝的转运，通过在赖氨酸 34 (RhoHK34A) 处引入 RhoH 突变，在破坏与 NMHC IIA 的相互作用后部分恢复。同时，RHOH 可能通过调节 RAC1 活性来抑制肌动蛋白聚合。使用 Rhoh-/- 小鼠进行的体内研究表明，对大肠杆菌 (E. coli) 的抗菌防御能力增强。总的来说，我们的数据揭示了 RHOH 作为肌动球蛋白介导的中性粒细胞效应功能的分子制动的先前未定义的作用，这代表了参与控制抗菌炎症反应强度的细胞内调节轴。

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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 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.

更新日期：2022-09-15

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