Feedback regulation by the RhoA-specific GEF ARHGEF17 regulates actomyosin network disassembly
Posted on: 18 September 2024
Preprint posted on 28 August 2024
Categories: cell biology
Background and hypothesis.
Rho GTPase family coordinates variations in cytoskeletal dynamics to drive cell and tissue morphogenesis. Cyclic activation and inactivation of Rho GTPase are controlled by upstream players like guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) respectively. Once active, GTP-bound state, Rho interacts with downstream effectors to modulate cytoskeletal dynamics and cellular processes.
Earlier studies delineated function of Rac1 in lamellipodial extension, Cdc42 in filopodial protrusion, and RhoA with myosin-driven contractility. However, with advancement in imaging techniques and FRET biosensors, revealed a more complex spatiotemporal pattern for Rho GTPases, fluctuating rapidly emphasizing existence of precise governing machinery. GEFs and GAPs are ubiquitous expression, distinct localisation and associated to cytoskeletal and adhesion structures further suggests a feedback role in Rho GTPase pattern formation.
Authors in this preprint hypothesize that ARHGEF17, a RhoA-specific GEF, has unique ability to bind ATP-actin at newly formed F-actin filaments, could mediate crosstalk between cytoskeletal and RhoA signaling.
Key findings.
ARHGEF17, via RhoA, controls lamella disassembly. A key finding of the preprint is that authors demonstrate specific localization of ARHGEF17, which is edge distal region of the lamella in fibroblast cells, where it interacts with areas with low myosin light chain (MLC) density, and facilitating disassembly of transverse actin arcs. ARHGEF17 oligomerizes into clusters which align with actomyosin networks. Utilizing structured illumination microscopy, authors found that these clusters colocalize with myosin filaments, creating distinct patterns based on spatial organization of actomyosin. ARHGEF17 cluster size and density advance from lamellipodia to cell centre. These finding confirms correlation between discrete actomyosin arrangements and levels of contractility.
ARHGEF17 clusters flow with the retrograde actin flow. Authors further confirm that ARHGEF17 clusters traffic with retrograde actin flow, and increase in intensity as they are transported. Retrograde actin flow is interrupted by disassembly of actomyosin transverse arcs in lamella, where ARHGEF17 is enriched. ArHGEF17 clustering likely activates RhoA-ROCK-MLC signaling, leading to local disassembly of low-contractile arcs rather than increasing contractility, suggesting a regulatory mechanism for actomyosin network dynamics.
RhoA activity in edge distal lamella is decreased upon removal of ARHGEF17. Despite unaffected RhoA activity at leading edge, ARHGEF17 loss of function reduces edge distal lamella RhoA activity, and impaired F-actin disassembly and actomyosin dynamics. This is a rather interesting finding confirming ARHGEF17 is able to regulate distinct pool of RhoA, hence governing both actin assembly and disassembly in different subcellular zones.
ARHGEF17 favorably binds to relaxed actomyosin networks. ARHGEF17 preferentially binds relaxed, disassembling actomyosin networks, in low-contractile regions of the cell. Using optogenetic manipulation and inhibition of ROCK activity, ARHGEF17 was recruited explicitly during actomyosin relaxation, confirming its ability to sense and associates to relaxed structures and regulating actin dynamics during network disassembly.
Significance of the Study.
# Findings from the preprint establishes a previously unknown mode of disassembly of actomyosin network regulated by ARHGEF17 in the low-contractile lamella region (Figure 1). It defies the conventional established view of RhoA only promoting actomyosin assembly and reveals ARHGEF17 is recruited for network disassembly. RhoA leads to the disassembly of actomyosin networks, rather than the assembly like is currently assumed. This goes against the dogma! This occurs because the ARHGEF17-Rho-ROCK-MLC mediated actomyosin contractility is specifically positioned on the relaxing actomyosin network!
# It also underscores that spatiotemporal signaling pathway is crucial for cytoskeletal dynamics and regulation of complexity of Rho signaling in various sub-cellular zones during fundamental processes.
# Comprehensive examination of ARHGEF17’s role in actomyosin disassembly have therapeutic potential in diseases associated to cytoskeletal dysfunction, such as fibrosis, cardiovascular diseases, and cancer. Furthermore, considering involvement of RhoA in numerous signaling pathways, moderating ARHGEF17 may perhaps offer a precise way to intervene in pathological developments.
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