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RHO GTPases: from new partners to complex immune syndromes

Nature Reviews Immunology volume 21, pages 499–513 (2021)Cite this article

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Abstract

Ras homology (RHO) GTPases are signalling proteins that have crucial roles in triggering multiple immune functions. Through their interactions with a broad range of effectors and kinases, they regulate cytoskeletal dynamics, cell polarity and the trafficking and proliferation of immune cells. The activity and localization of RHO GTPases are highly controlled by classical families of regulators that share consensus motifs. In this Review, we describe the recent discovery of atypical modulators and partners of RHO GTPases, which bring an additional layer of regulation and plasticity to the control of RHO GTPase activities in the immune system. Furthermore, the development of large-scale genetic screening has now enabled researchers to identify dysregulation of RHO GTPase signalling pathways as a cause of many immune system-related diseases. We discuss the mutations that have been identified in RHO GTPases and their signalling circuits in patients with rare diseases. The discoveries of new RHO GTPase partners and genetic mutations in RHO GTPase signalling hubs have uncovered unsuspected layers of crosstalk with other signalling pathways and may provide novel therapeutic opportunities for patients affected by complex immune or broader syndromes.

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Fig. 1: Synthesis, post-translational modifications and typical mechanisms of action of RHO GTPases.
Fig. 2: Model of RHOA and RAC1 regulation by the atypical negative regulators FAM65A, FAM65B and FAM49B.
Fig. 3: RHO GTPase signalling networks involving novel effector proteins.
Fig. 4: RHO GTPases and their partner proteins mutated in human diseases.
Fig. 5: Position of the diverse mutations of CDC42 identified in patients.

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Acknowledgements

This work was supported by Inserm, CNRS, Université de Paris, the French Agence Nationale de la Recherche, Société Française de Dermatologie, Programme Germaine de Stael and Fondation ARC. The authors thank E. Bloch-Gallego, M. Mangeney and C. Randriamampita for critical reading of the manuscript. The authors apologize to colleagues whose work could not be cited owing to space limitations.

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  1. Université de Paris, Institut Cochin, Inserm, CNRS, Paris, France

    Rana El Masri & Jérôme Delon

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Supplementary information

Glossary

SCAR/WAVE proteins

Suppressor of cAMP receptor/Wiskott–Aldrich syndrome protein (WASp) family verprolin homology proteins. A complex of WASp family-related proteins that are implicated in the regulation of cytoskeletal organization, lamellipodium formation, actin dynamics and cell motility through the activation of actin-related protein 2/3 (ARP2/3) complex-dependent actin nucleation.

Pseudopod

A filamentous actin-rich projection of the cell membrane of leukocytes formed to trigger cell migration and to direct their movement in response to a chemoattractive stimulus.

Ezrin/radixin/moesin proteins

(ERM proteins). Highly homologous proteins involved in multiple cellular processes, notably cell migration and activation, by crosslinking plasma membrane proteins to the underlying cortical actin cytoskeleton when they adopt an open conformation upon phosphorylation.

Marginal zone B cells

A subpopulation of B cells localized in the spleen and lymph nodes at the site of exposure to antigens, where they can rapidly proliferate and differentiate into IgM+ plasmablasts.

RNA processing bodies

(P-bodies). Cytoplasmic aggregates composed of mRNA and proteins that are involved in mRNA decay and translation repression.

Septins

Guanosine triphosphate (GTP)-binding, membrane-interacting proteins that are highly conserved components of the cytoskeletal system and are involved in multiple cellular processes, including cytokinesis, cell polarity and membrane dynamics, through their capacity to adopt variable architectures.

TCR excision circles

Small circular DNA fragments generated by developing T cells in the thymus as a product of the rearrangement of gene segments encoding the variable domains of the T cell receptor (TCR).

Wiskott–Aldrich syndrome protein

(WASp). A cytoplasmic signalling protein expressed in haematopoietic cells that regulates the actin cytoskeleton through the control of actin-related protein 2/3 (ARP2/3) complex activity and that participates in both innate and adaptive immune responses.

Somatic reversion

Genetic mechanism by which a DNA mutation is repaired to give back a normal protein.

Switch II domain

A region of the Ras homology (RHO) GTPases that has the capacity to change its conformation according to the nature of the bound phosphate group (guanosine diphosphate (GDP) or guanosine triphosphate (GTP)), which switches the activity state of the protein and affects its interaction with regulator and effector proteins.

Noonan syndrome

A common genetic multisystem disorder characterized by variable phenotypes, including typical facial features, developmental delay, short stature, congenital heart defects, renal anomalies, lymphatic malformations, bleeding difficulties and learning disabilities, caused by mutations in the genes encoding proteins involved in the RAS–mitogen-activated protein kinase signalling pathway.

Familial Mediterranean fever syndrome

An autoinflammatory disease caused by mutations in MEFV, which encodes a 781 amino acid protein known as pyrin.

Actin-related protein 2/3 complex

(ARP2/3 complex). A seven-subunit conserved protein complex that nucleates branched actin filament networks and finely regulates their organization in crucial cellular functions, including cell migration, endocytosis, phagocytosis, vesicular trafficking and cytokinesis, through its interaction with nucleation-promoting factors such as Wiskott–Aldrich syndrome protein (WASp) and the SCAR/WAVE proteins.

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El Masri, R., Delon, J. RHO GTPases: from new partners to complex immune syndromes. Nat Rev Immunol 21, 499–513 (2021). https://doi.org/10.1038/s41577-021-00500-7

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