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Role of RhoG as a regulator of cellular functions: integrating insights on immune cell activation, migration, and functions

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Abstract

Background

RhoG is a multifaceted member of the Rho family of small GTPases, sharing the highest sequence identity with the Rac subfamily members. It acts as a molecular switch, when activated, plays a central role in regulating the fundamental processes in immune cells, such as actin-cytoskeleton dynamics, transendothelial migration, survival, and proliferation, including immunological functions (e.g., phagocytosis and trogocytosis) during inflammatory responses.

Method

We have performed a literature review based on published original and review articles encompassing the significant effect of RhoG on immune cell functions from central databases, including PubMed and Google Scholar.

Results and conclusions

Recently published data shows that the dynamic expression of different transcription factors, non-coding RNAs, and the spatiotemporal coordination of different GEFs with their downstream effector molecules regulates the cascade of Rho signaling in immune cells. Additionally, alterations in RhoG-specific signaling can lead to physiological, pathological, and developmental adversities. Several mutations and RhoG-modulating factors are also known to pre-dispose the downstream signaling with abnormal gene expression linked to multiple diseases. This review focuses on the cellular functions of RhoG, interconnecting different signaling pathways, and speculates the importance of this small GTPase as a prospective target against several pathological conditions.

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No data were used for the research described in the article.

References

  1. Hervé JC, Bourmeyster N. Rho GTPases at the crossroad of signaling networks in mammals. Small GTPases. 2015;6:43–8.

    Article  PubMed  PubMed Central  Google Scholar 

  2. Colicelli J. Human RAS superfamily proteins and related GTPases. Science's STKE : signal transduction knowledge environment 2004; 2004:Re13.

  3. Nayak RC, Chang KH, Vaitinadin NS, Cancelas JA. Rho GTPases control specific cytoskeleton-dependent functions of hematopoietic stem cells. Immunol Rev. 2013;256:255–68.

    Article  CAS  PubMed  Google Scholar 

  4. Dipankar P, Kumar P, Dash SP, Sarangi PP. Functional and Therapeutic Relevance of Rho GTPases in Innate Immune Cell Migration and Function during Inflammation: An In Silico Perspective. Mediators of inflammation 2021; 2021:6655412.

  5. Haga RB, Ridley AJ. Rho GTPases: Regulation and roles in cancer cell biology. Small GTPases. 2016;7:207–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Gauthier-Rouvière C, Vignal E, Mériane M, Roux P, Montcourier P, Fort P. RhoG GTPase controls a pathway that independently activates Rac1 and Cdc42Hs. Mol Biol Cell. 1998;9:1379–94.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Steffen A, Ladwein M, Dimchev GA, Hein A, Schwenkmezger L, Arens S, et al. Rac function is crucial for cell migration but is not required for spreading and focal adhesion formation. J Cell Sci. 2013;126:4572–88.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Vigorito E, Billadeu DD, Savoy D, McAdam S, Doody G, Fort P, et al. RhoG regulates gene expression and the actin cytoskeleton in lymphocytes. Oncogene. 2003;22:330–42.

    Article  CAS  PubMed  Google Scholar 

  9. Katoh H, Hiramoto K, Negishi M. Activation of Rac1 by RhoG regulates cell migration. J Cell Sci. 2006;119:56–65.

    Article  CAS  PubMed  Google Scholar 

  10. Murga C, Zohar M, Teramoto H, Gutkind JS. Rac1 and RhoG promote cell survival by the activation of PI3K and Akt, independently of their ability to stimulate JNK and NF-kappaB. Oncogene. 2002;21:207–16.

    Article  CAS  PubMed  Google Scholar 

  11. Vincent S, Jeanteur P, Fort P. Growth-regulated expression of rhoG, a new member of the ras homolog gene family. Mol Cell Biol. 1992;12:3138–48.

    CAS  PubMed  PubMed Central  Google Scholar 

  12. Schumacher S, Franke K. miR-124-regulated RhoG: A conductor of neuronal process complexity. Small GTPases. 2013;4:42–6.

    Article  PubMed  PubMed Central  Google Scholar 

  13. Bos JL, Rehmann H, Wittinghofer A. GEFs and GAPs: critical elements in the control of small G proteins. Cell. 2007;129:865–77.

    Article  CAS  PubMed  Google Scholar 

  14. Cherfils J, Zeghouf M. Regulation of small GTPases by GEFs, GAPs, and GDIs. Physiol Rev. 2013;93:269–309.

    Article  CAS  PubMed  Google Scholar 

  15. Ridley AJ. Rho GTPases and actin dynamics in membrane protrusions and vesicle trafficking. Trends Cell Biol. 2006;16:522–9.

    Article  CAS  PubMed  Google Scholar 

  16. Roux P, Gauthier-Rouvière C, Doucet-Brutin S, Fort P. The small GTPases Cdc42Hs, Rac1 and RhoG delineate Raf-independent pathways that cooperate to transform NIH3T3 cells. Current biology : CB. 1997;7:629–37.

    Article  CAS  PubMed  Google Scholar 

  17. Wennerberg K, Ellerbroek SM, Liu RY, Karnoub AE, Burridge K, Der CJ. RhoG signals in parallel with Rac1 and Cdc42. J Biol Chem. 2002;277:47810–7.

    Article  CAS  PubMed  Google Scholar 

  18. Brugnera E, Haney L, Grimsley C, Lu M, Walk SF, Tosello-Trampont AC, et al. Unconventional Rac-GEF activity is mediated through the Dock180-ELMO complex. Nat Cell Biol. 2002;4:574–82.

    Article  CAS  PubMed  Google Scholar 

  19. van Rijssel J, Hoogenboezem M, Wester L, Hordijk PL, Van Buul JD. The N-terminal DH-PH domain of Trioinduces cell spreading and migration by regulating lamellipodia dynamics in a Rac1-dependent fashion. PLoS ONE. 2012;7: e29912.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Blangy A, Vignal E, Schmidt S, Debant A, Gauthier-Rouvière C, Fort P. TrioGEF1 controls Rac- and Cdc42-dependent cell structures through the direct activation of rhoG. J Cell Sci. 2000;113(Pt 4):729–39.

    Article  CAS  PubMed  Google Scholar 

  21. Baumeister MA, Rossman KL, Sondek J, Lemmon MA. The Dbs PH domain contributes independently to membrane targeting and regulation of guanine nucleotide-exchange activity. Biochem J. 2006;400:563–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Jaiswal M, Dvorsky R, Ahmadian MR. Deciphering the molecular and functional basis of Dbl family proteins: a novel systematic approach toward classification of selective activation of the Rho family proteins. J Biol Chem. 2013;288:4486–500.

    Article  CAS  PubMed  Google Scholar 

  23. Fuentes EJ, Karnoub AE, Booden MA, Der CJ, Campbell SL. Critical role of the pleckstrin homology domain in Dbs signaling and growth regulation. J Biol Chem. 2003;278:21188–96.

    Article  CAS  PubMed  Google Scholar 

  24. Bircher JE, Koleske AJ. (2021) Trio family proteins as regulators of cell migration and morphogenesis in development and disease - mechanisms and cellular contexts. Journal of cell science 134.

  25. Schuebel KE, Movilla N, Rosa JL, Bustelo XR. Phosphorylation-dependent and constitutive activation of Rho proteins by wild-type and oncogenic Vav-2. EMBO J. 1998;17:6608–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Movilla N, Bustelo XR. Biological and regulatory properties of Vav-3, a new member of the Vav family of oncoproteins. Mol Cell Biol. 1999;19:7870–85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Ellerbroek SM, Wennerberg K, Arthur WT, Dunty JM, Bowman DR, DeMali KA, et al. SGEF, a RhoG guanine nucleotide exchange factor that stimulates macropinocytosis. Mol Biol Cell. 2004;15:3309–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. May V, Schiller MR, Eipper BA, Mains RE. Kalirin Dbl-homology guanine nucleotide exchange factor 1 domain initiates new axon outgrowths via RhoG-mediated mechanisms. J Neurosci Off J Soc Neurosci. 2002;22:6980–90.

    Article  CAS  Google Scholar 

  29. Kim K, Lee J, Moon H, Lee SA, Kim D, Yang S, et al. (2018) The Intermolecular Interaction of Ephexin4 Leads to Autoinhibition by Impeding Binding of RhoG. Cells 7.

  30. Hiramoto-Yamaki N, Takeuchi S, Ueda S, Harada K, Fujimoto S, Negishi M, et al. Ephexin4 and EphA2 mediate cell migration through a RhoG-dependent mechanism. J Cell Biol. 2010;190:461–77.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Komiya Y, Onodera Y, Kuroiwa M, Nomimura S, Kubo Y, Nam JM, et al. The Rho guanine nucleotide exchange factor ARHGEF5 promotes tumor malignancy via epithelial-mesenchymal transition. Oncogenesis. 2016;5: e258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Wang Z, Kumamoto Y, Wang P, Gan X, Lehmann D, Smrcka AV, et al. Regulation of immature dendritic cell migration by RhoA guanine nucleotide exchange factor Arhgef5. J Biol Chem. 2009;284:28599–606.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Lemmon MA, Ferguson KM, Abrams CS. Pleckstrin homology domains and the cytoskeleton. FEBS Lett. 2002;513:71–6.

    Article  CAS  PubMed  Google Scholar 

  34. Bagci H, Sriskandarajah N, Robert A, Boulais J, Elkholi IE, Tran V, et al. Mapping the proximity interaction network of the Rho-family GTPases reveals signalling pathways and regulatory mechanisms. Nat Cell Biol. 2020;22:120–34.

    Article  CAS  PubMed  Google Scholar 

  35. Garcia-Mata R, Boulter E, Burridge K. The “invisible hand”: regulation of RHO GTPases by RHOGDIs. Nat Rev Mol Cell Biol. 2011;12:493–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Zalcman G, Closson V, Camonis J, Honoré N, Rousseau-Merck MF, Tavitian A, (1996) et al. RhoGDI-3 is a new GDP dissociation inhibitor (GDI). Identification of a non-cytosolic GDI protein interacting with the small GTP-binding proteins RhoB and RhoG. The Journal of biological chemistry 271:30366–74.

  37. Estrach S, Schmidt S, Diriong S, Penna A, Blangy A, Fort P, et al. The Human Rho-GEF trio and its target GTPase RhoG are involved in the NGF pathway, leading to neurite outgrowth. Current biology : CB. 2002;12:307–12.

    Article  CAS  PubMed  Google Scholar 

  38. Marignani PA, Carpenter CL. Vav2 is required for cell spreading. J Cell Biol. 2001;154:177–86.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Prisco A, Vanes L, Ruf S, Trigueros C, Tybulewicz VL. Lineage-specific requirement for the PH domain of Vav1 in the activation of CD4+ but not CD8+ T cells. Immunity. 2005;23:263–74.

    Article  CAS  PubMed  Google Scholar 

  40. Lee J, Park B, Kim G, Kim K, Pak J, Kim K, et al. Arghef16, a novel Elmo1 binding partner, promotes clearance of apoptotic cells via RhoG-dependent Rac1 activation. Biochim Biophys Acta. 2014;1843:2438–47.

    Article  CAS  PubMed  Google Scholar 

  41. Brunet N, Morin A, Olofsson B. RhoGDI-3 regulates RhoG and targets this protein to the Golgi complex through its unique N-terminal domain. Traffic (Copenhagen, Denmark). 2002;3:342–57.

    Article  CAS  PubMed  Google Scholar 

  42. Brisac C, Salloum S, Yang V, Schaefer EA, Holmes JA, Chevaliez S, et al. IQGAP2 is a novel interferon-alpha antiviral effector gene acting non-conventionally through the NF-κB pathway. J Hepatol. 2016;65:972–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Vigorito E, Bell S, Hebeis BJ, Reynolds H, McAdam S, Emson PC, et al. Immunological function in mice lacking the Rac-related GTPase RhoG. Mol Cell Biol. 2004;24:719–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  44. Martínez-Martín N, Fernández-Arenas E, Cemerski S, Delgado P, Turner M, Heuser J, et al. T cell receptor internalization from the immunological synapse is mediated by TC21 and RhoG GTPase-dependent phagocytosis. Immunity. 2011;35:208–22.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Vaeth M, Feske S. (2018) NFAT control of immune function: New Frontiers for an Abiding Trooper. F1000Research; 7:260.

  46. Charpentier JC, King PD. Mechanisms and functions of endocytosis in T cells. Cell Commun Signal. 2021;19:92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Prieto-Sánchez RM, Bustelo XR. Structural basis for the signaling specificity of RhoG and Rac1 GTPases. J Biol Chem. 2003;278:37916–25.

    Article  PubMed  Google Scholar 

  48. Macián F, García-Cózar F, Im SH, Horton HF, Byrne MC, Rao A. Transcriptional mechanisms underlying lymphocyte tolerance. Cell. 2002;109:719–31.

    Article  PubMed  Google Scholar 

  49. Hogan PG. Calcium-NFAT transcriptional signalling in T cell activation and T cell exhaustion. Cell Calcium. 2017;63:66–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. de León-Bautista MP, Cardenas-Aguayo MD, Casique-Aguirre D, Almaraz-Salinas M, Parraguirre-Martinez S, Olivo-Diaz A, et al. Immunological and functional characterization of RhoGDI3 and Its molecular Targets RhoG and RhoB in human pancreatic cancerous and normal cells. PLoS ONE. 2016;11: e0166370.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Oh HM, Yu CR, Golestaneh N, Amadi-Obi A, Lee YS, Eseonu A, et al. STAT3 protein promotes T-cell survival and inhibits interleukin-2 production through up-regulation of Class O Forkhead transcription factors. J Biol Chem. 2011;286:30888–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lämmermann T, Germain RN. The multiple faces of leukocyte interstitial migration. Seminars in immunopathology. 2014;36:227–51.

    Article  PubMed  PubMed Central  Google Scholar 

  53. Welch HC, Condliffe AM, Milne LJ, Ferguson GJ, Hill K, Webb LM, et al. P-Rex1 regulates neutrophil function. Current biology : CB. 2005;15:1867–73.

    Article  CAS  PubMed  Google Scholar 

  54. Lawson CD, Donald S, Anderson KE, Patton DT, Welch HC. (2011) P-Rex1 and Vav1 cooperate in the regulation of formyl-methionyl-leucyl-phenylalanine-dependent neutrophil responses. Journal of immunology (Baltimore, Md : 1950); 186:1467–76.

  55. Welch HC, Coadwell WJ, Ellson CD, Ferguson GJ, Andrews SR, Erdjument-Bromage H, et al. P-Rex1, a PtdIns(3,4,5)P3- and Gbetagamma-regulated guanine-nucleotide exchange factor for Rac. Cell. 2002;108:809–21.

    Article  CAS  PubMed  Google Scholar 

  56. Pantarelli C, Welch HCE. Rac-GTPases and Rac-GEFs in neutrophil adhesion, migration and recruitment. Eur J Clin Invest. 2018;48(Suppl 2): e12939.

    Article  PubMed  PubMed Central  Google Scholar 

  57. Condliffe AM, Webb LM, Ferguson GJ, Davidson K, Turner M, Vigorito E, et al. (2006) RhoG regulates the neutrophil NADPH oxidase. Journal of immunology (Baltimore, Md : 1950); 176:5314–20.

  58. Mao Y, Finnemann SC. Regulation of phagocytosis by Rho GTPases. Small GTPases. 2015;6:89–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Tzircotis G, Braga VM, Caron E. RhoG is required for both FcγR- and CR3-mediated phagocytosis. J Cell Sci. 2011;124:2897–902.

    Article  CAS  PubMed  Google Scholar 

  60. Muller WA. Mechanisms of leukocyte transendothelial migration. Annu Rev Pathol. 2011;6:323–44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Rougerie P, Miskolci V, Cox D. Generation of membrane structures during phagocytosis and chemotaxis of macrophages: role and regulation of the actin cytoskeleton. Immunol Rev. 2013;256:222–39.

    Article  CAS  PubMed  Google Scholar 

  62. Kalinichenko A, Perinetti Casoni G, Dupré L, Trotta L, Huemer J, Galgano D, et al. RhoG deficiency abrogates cytotoxicity of human lymphocytes and causes hemophagocytic lymphohistiocytosis. Blood. 2021;137:2033–45.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Damoulakis G, Gambardella L, Rossman KL, Lawson CD, Anderson KE, Fukui Y, et al. P-Rex1 directly activates RhoG to regulate GPCR-driven Rac signalling and actin polarity in neutrophils. J Cell Sci. 2014;127:2589–600.

    CAS  PubMed  Google Scholar 

  64. Welch HC. Regulation and function of P-Rex family Rac-GEFs. Small GTPases. 2015;6:49–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Galluzzi L, Vitale I, Aaronson SA, Abrams JM, Adam D, Agostinis P, et al. Molecular mechanisms of cell death: recommendations of the nomenclature committee on cell death 2018. Cell Death Differ. 2018;25:486–541.

    Article  PubMed  PubMed Central  Google Scholar 

  66. Taddei ML, Giannoni E, Fiaschi T, Chiarugi P. Anoikis: an emerging hallmark in health and diseases. J Pathol. 2012;226:380–93.

    Article  CAS  PubMed  Google Scholar 

  67. Yamaki N, Negishi M, Katoh H. RhoG regulates anoikis through a phosphatidylinositol 3-kinase-dependent mechanism. Exp Cell Res. 2007;313:2821–32.

    Article  CAS  PubMed  Google Scholar 

  68. Harada K, Hiramoto-Yamaki N, Negishi M, Katoh H. Ephexin4 and EphA2 mediate resistance to anoikis through RhoG and phosphatidylinositol 3-kinase. Exp Cell Res. 2011;317:1701–13.

    Article  CAS  PubMed  Google Scholar 

  69. Dipankar P, Kumar P, Sarangi PP. (2023) In silico identification and characterization of small-molecule inhibitors specific to RhoG/Rac1 signaling pathway. Journal of biomolecular structure and dynamics; 41:560–580.

  70. Williams DA, Tao W, Yang F, Kim C, Gu Y, Mansfield P, et al. Dominant negative mutation of the hematopoietic-specific Rho GTPase, Rac2, is associated with a human phagocyte immunodeficiency Blood. J Am Soc Hematology. 2000;96:1646–54.

    CAS  Google Scholar 

  71. Ahmad Mokhtar AM, Salikin NH, Haron AS, Amin-Nordin S, Hashim IF, Mohd Zaini Makhtar M, et al. (2022) RhoG’s role in T cell activation and function. Frontiers in Immunology 13:845064.

  72. Utech M, Höbbel G, Rust S, Reinecke H, Assmann G, Walter M. Accumulation of RhoA, RhoB, RhoG, and Rac1 in fibroblasts from Tangier disease subjects suggests a regulatory role of Rho family proteins in cholesterol efflux. Biochem Biophys Res Commun. 2001;280:229–36.

    Article  CAS  PubMed  Google Scholar 

  73. Lougaris V, Baronio M, Gazzurelli L, Benvenuto A, Plebani A. RAC2 and primary human immune deficiencies. J Leucocyte Bio. 2020;108:687–96.

    Article  CAS  Google Scholar 

  74. Weksler B, Lu B. Alterations of the immune system in thymic malignancies. J Thorac Oncol. 2014;9:S137–42.

    Article  PubMed  Google Scholar 

  75. Bishop AL, Hall A. Rho GTPases and their effector proteins. Biochemical J. 2000;348:241–55.

    Article  CAS  Google Scholar 

  76. Roux P, Gauthier-Rouvière C, Doucet-Brutin S, Fort P. The small GTPases Cdc42Hs, Rac1 and RhoG delineate Raf-independent pathways that cooperate to transform NIH3T3 cells. Curr Biol. 1997;7:629–37.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the Science Engineering Research Board, Govt. of India (CRG-2020-0025), to PPS; DBT fellowship to SKR. The authors would like to thank Dr. Prerna Sharma for her critical comments on the manuscript.

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  1. Shubham Kumar Rai and Divya Singh have contributed equally to the work.

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  1. Department of Biosciences and Bioengineering, Indian Institute of Technology Roorkee, Roorkee, Uttarakhand, 247667, India

    Shubham Kumar Rai, Divya Singh & Pranita P. Sarangi

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  1. Shubham Kumar Rai
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SKR and DS have searched the literature, prepared the figures, and written the manuscript. PPS has organized and edited the manuscript.

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Correspondence to Pranita P. Sarangi.

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Rai, S.K., Singh, D. & Sarangi, P.P. Role of RhoG as a regulator of cellular functions: integrating insights on immune cell activation, migration, and functions. Inflamm. Res. 72, 1453–1463 (2023). https://doi.org/10.1007/s00011-023-01761-9

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