The Role of RhoH in TCR Signalling and Its Involvement in Diseases

Abstract

As an atypical member of the Rho family small GTPases, RhoH shares less than 50% sequence similarity with other members, and its expression is commonly observed in the haematopoietic lineage. To date, RhoH function was observed in regulating T cell receptor signalling, and less is known in other haematopoietic cells. Its activation may not rely on the standard GDP/GTP cycling of small G proteins and is thought to be constitutively active because critical amino acids involved in GTP hydrolysis are absent. Alternatively, its activation can be regulated by other types of regulation, including lysosomal degradation, somatic mutation and transcriptional repressor, which also results in an altered protein expression. Aberrant protein expression of RhoH has been implicated not only in B cell malignancies but also in immune-related diseases, such as primary immunodeficiencies, systemic lupus erythematosus and psoriasis, wherein its involvement may provide the link between immune-related diseases and cancer. RhoH association with these diseases involves several other players, including its interacting partner, ZAP−70; activation regulators, Vav1 and RhoGDI and other small GTPases, such as RhoA, Rac1 and Cdc42. As such, RhoH and its associated proteins are potential attack points, especially in the treatment of cancer and immune-related diseases.

Identification of biological pathways and processes regulated by NEK5 in breast epithelial cells via an integrated proteomic approach

“…4A). However, an interesting finding was the enrichment for the RhoH GTPase cycle, which appears to reflect the presence of cytoskeletal regulators rather than RhoH itself, which is specific to the hematopoietic system [42]. The BioID approach also identified a variety of signalling proteins as NEK5 interactors.…”

Pathophysiological Mechanisms in Neurodevelopmental Disorders Caused by Rac GTPases Dysregulation: What’s behind Neuro-RACopathies

“…Twenty small Rho family guanosine triphosphatases (GTPases) have been identified in humans, classified in eight major subfamilies based on structural and biological properties: Rho-, Rac-, Cdc42-, RhoU/RhoV-, Rnd-, RhoD/R-, hoF-, RhoBTB-, and RhoH subfamilies [ 1 , 2 ]. As relevant key regulators of cytoskeletal dynamics and intracellular signaling, Rho family guanosine triphosphatases (GTPases) are crucial for the regulation of several fundamental biological processes in various cell types, including cell cycle progression, gene transcription, and cell morphology, motility, and polarity [ 3 ].…”

“…While GEFs promote the dissociation of GDP and the binding of GTP, resulting in the activated state of the protein, GAPs stimulate the intrinsic GTPase activity and the GTP hydrolysis, thus terminating the signaling and completing the cycle [ 13 , 14 ]. Acting as negative regulators, GDIs are instead essential to regulate the amount of available GTPases and also modulate their targeting to intracellular compartments [ 1 , 2 ]. Once in the active state, the GTPases can activate several distinct downstream effectors, ranging from actin-related proteins to kinases ( Figure 2 ) [ 15 ].…”

Discovery and Structural Optimization of Covalent ZAP-70 Kinase Inhibitors against Psoriasis

“…Psoriasis is a complex and chronic inflammatory skin disease that impacts approximately 2% of the global population. − It is widely recognized as an autoimmune-related disease resulting from immune system dysregulation. , The pathogenesis of psoriasis is characterized by the activation of immune cells, primarily T cells, abnormal differentiation of keratinocytes, and aberrant release of inflammatory cytokines. ,, Despite the availability of various therapies, including topical agents, systemic or biologic therapies, and phototherapy, the management of psoriasis remains a challenge. , This is due in part to severe side effects associated with some medications, as well as poor patient compliance and the high cost of certain therapies. , Thus, novel therapeutic targets and drugs for the treatment of psoriasis are still needed. Given the important role of the T cell receptor (TCR) signaling pathway in the immune system, targeted inhibition of the TCR signal with small-molecule drugs appears to be a potential alternative strategy for the treatment of psoriasis. − …”

“…Although several classes of ZAP-70 inhibitors have been reported (Figure ), most of these compounds ( 1 – 5 ) display low potency against ZAP-70 kinase and lack selectivity over other kinases, particularly its homologous protein Syk. − Furthermore, none of the ZAP-70 inhibitors have demonstrated efficacy in vivo in animal models of autoimmune-related diseases. Therefore, there is an urgent demand for the development of novel ZAP-70 inhibitors with higher safety and potency to investigate their efficacy in vivo and assess the potential of ZAP-70 as a promising drug target for treating autoimmune disorders, including psoriasis …”