RhoH, an atypical member of the Rho family small GTPases, is predominantly expressed in the hematopoietic lineage. Lacking GTPase activity, it is constitutively active and is crucial for regulating T cell receptor signalling. RhoH also participates in multiple cellular functions through interactions with proteins like ZAP-70, Vav1, RhoGDI, and other small GTPases such as RhoA, Rac1, and Cdc42 [1]. Its abnormal expression is linked to B cell malignancies and immune-related diseases like primary immunodeficiencies, systemic lupus erythematosus, and psoriasis [1].

In gene knockout studies, Rhoh-/-mice showed accelerated disease progression in a murine model of Bcl-6 driven DLBCL. Deletion of Rhoh led to decreased levels of KAISO, de-repression of Bcl-6, and down-regulation of Blimp-1 [3]. Rhoh-/-mice also demonstrated increased antibacterial defense against E. coli as RhoH normally acts as a molecular brake on neutrophil degranulation and NET formation [2]. In a murine allogenic kidney transplantation model, Rhoh deficiency significantly reduced acute and chronic transplant rejection, accompanied by lower alloantigen-specific antibody levels and better graft function [4].

In conclusion, RhoH is a key regulator in the hematopoietic system, playing important roles in T cell function, neutrophil effector functions, and disease-related processes such as lymphoma progression and transplant rejection. Gene knockout mouse models have been instrumental in revealing these functions, highlighting RhoH's potential as a therapeutic target in cancer and immune-related diseases.

References:

1. Ahmad Mokhtar, Ana Masara, Hashim, Ilie Fadzilah, Mohd Zaini Makhtar, Muaz, Salikin, Nor Hawani, Amin-Nordin, Syafinaz. 2021. The Role of RhoH in TCR Signalling and Its Involvement in Diseases. In Cells, 10, . doi:10.3390/cells10040950. https://pubmed.ncbi.nlm.nih.gov/33923951/

2. Peng, Shuang, Stojkov, Darko, Gao, Jian, Yousefi, Shida, Simon, Hans-Uwe. 2022. Nascent RHOH acts as a molecular brake on actomyosin-mediated effector functions of inflammatory neutrophils. In PLoS biology, 20, e3001794. doi:10.1371/journal.pbio.3001794. https://pubmed.ncbi.nlm.nih.gov/36108062/

3. Horiguchi, Hiroto, Xu, Haiming, Duvert, Beatrice, Chiarle, Roberto, Williams, David A. . Deletion of murine Rhoh leads to de-repression of Bcl-6 via decreased KAISO levels and accelerates a malignancy phenotype in a murine model of lymphoma. In Small GTPases, 13, 267-281. doi:10.1080/21541248.2021.2019503. https://pubmed.ncbi.nlm.nih.gov/34983288/

4. Porubsky, Stefan, Wang, Shijun, Kiss, Eva, Brakebusch, Cord, Gröne, Hermann-Josef. 2010. Rhoh deficiency reduces peripheral T-cell function and attenuates allogenic transplant rejection. In European journal of immunology, 41, 76-88. doi:10.1002/eji.201040420. https://pubmed.ncbi.nlm.nih.gov/21182079/