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ABSTRACT Regulator of G‐protein signalling (RGS) 10 plays critical roles in several immune related diseases. However, whether RGS10 is involved in colonic inflammation of ulcerative colitis (UC) is still obscure. This study aimed to investigate the role of RGS10 in UC. In this study, RGS10 expression was examined by quantitative real‐time polymerase chain reaction (qRT‐PCR), western blotting, immunohistochemistry, and immunofluorescent analysis. Single‐cell RNA sequencing of intestinal mucosa was performed to identify key immune cells with differentially expressed RGS10. RGS10 knockout mice were generated and established dextran sulphate sodium (DSS)‐induced colitis. Expression of inflammatory cytokines on mRNA and protein levels was detected by qRT‐PCR, enzyme‐linked immunosorbent assay, and flow cytometry. We found that RGS10 expression was significantly elevated in UC patients, especially in CD4+ T cells, compared with healthy subjects. Intriguingly, RGS10 deficiency markedly alleviated DSS‐induced colitis and decreased the proportion of Th1 and Th17 cells in lamina propria mononuclear cells (LPMCs), peripheral blood (PB), spleens, and mesenteric lymph nodes (mLNs). Mechanistically, RGS10 deficiency blocked the differentiation of Th1 and Th17 cells by inhibiting the phosphorylation of signal transducer and activator of transcription (STAT) 1 and STAT3. The co‐immunoprecipitation analysis further showed that RGS10 could interact with protein tyrosine phosphatase non‐receptor type 2 (PTPN2), and further regulated Th1 and Th17 cells differentiation of CD4+ T cells. In conclusion, RGS10 deficiency alleviated intestinal mucosal inflammation through inhibition of Th1/Th17 cell‐mediated immune responses via interaction with PTPN2 in CD4+ T cells. Therefore, targeting RGS10 may represent a novel therapeutic approach for UC treatment. [ABSTRACT FROM AUTHOR]

Distant metastasis is the major cause of death in patients with breast cancer. Epithelial–mesenchymal transition (EMT) contributes to breast cancer metastasis. Regulator of G protein-signaling (RGS) proteins modulates metastasis in various cancers. This study identified a novel role for RGS10 in EMT and metastasis in breast cancer. RGS10 protein levels were significantly lower in breast cancer tissues compared to normal breast tissues, and deficiency in RGS10 protein predicted a worse prognosis in patients with breast cancer. RGS10 protein levels were lower in the highly aggressive cell line MDA-MB-231 than in the poorly aggressive, less invasive cell lines MCF7 and SKBR3. Silencing RGS10 in SKBR3 cells enhanced EMT and caused SKBR3 cell migration and invasion. The ability of RGS10 to suppress EMT and metastasis in breast cancer was dependent on lipocalin-2 and MIR539-5p. These findings identify RGS10 as a tumor suppressor, prognostic biomarker, and potential therapeutic target for breast cancer.

Objective: Excessive proliferation and migration of pulmonary arterial smooth muscle cell (PASMC) is a core event of pulmonary hypertension (PH). Regulators of G protein signaling 10 (RGS10) can regulate cellular proliferation and cardiopulmonary diseases. We demonstrate whether RGS10 also serves as a regulator of PH. Methods: PASMC was challenged by hypoxia to induce proliferation and migration. Adenovirus carrying Rgs10 gene (Ad-Rgs10) was used for external expression of Rgs10. Hypoxia/SU5416 or MCT was used to induce PH. Right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) were used to validate the establishment of PH model. Results: RGS10 was downregulated in hypoxia-challenged PASMC. Ad-Rgs10 significantly suppressed proliferation and migration of PASMC after hypoxia stimulus, while silencing RGS10 showed contrary effect. Mechanistically, we observed that phosphorylation of S6 and 4E-Binding Protein 1 (4EBP1), the main downstream effectors of mammalian target of rapamycin complex 1 (mTORC1) as well as phosphorylation of AKT, the canonical upstream of mTORC1 in hypoxia-induced PASMC were negatively modulated by RGS10. Both recovering mTORC1 activity and restoring AKT activity abolished these effects of RGS10 on PASMC. More importantly, AKT activation also abolished the inhibitory role of RGS10 in mTORC1 activity in hypoxia-challenged PASMC. Finally, we also observed that overexpression of RGS10 in vivo ameliorated pulmonary vascular wall thickening and reducing RVSP and RVHI in mouse PH model. Conclusion: Our findings reveal the modulatory role of RGS10 in PASMC and PH via AKT/mTORC1 axis. Therefore, targeting RGS10 may serve as a novel potent method for the prevention against PH.". [ABSTRACT FROM AUTHOR]

Distant metastasis is the major cause of death in patients with breast cancer. Epithelial-mesenchymal transition (EMT) contributes to breast cancer metastasis. Regulator of G protein-signaling (RGS) proteins modulates metastasis in various cancers. This study identified a novel role for RGS10 in EMT and metastasis in breast cancer. RGS10 protein levels were significantly lower in breast cancer tissues compared to normal breast tissues, and deficiency in RGS10 protein predicted a worse prognosis in patients with breast cancer. RGS10 protein levels were lower in the highly aggressive cell line MDA-MB-231 than in the poorly aggressive, less invasive cell lines MCF7 and SKBR3. Silencing RGS10 in SKBR3 cells enhanced EMT and caused SKBR3 cell migration and invasion. The ability of RGS10 to suppress EMT and metastasis in breast cancer was dependent on lipocalin-2 and MIR539-5p . These findings identify RGS10 as a tumor suppressor, prognostic biomarker, and potential therapeutic target for breast cancer., Competing Interests: YL, YJ, PQ, TM, YB, JB, YH, MJ, TZ, XG No competing interests declared, (© 2024, Liu, Jiang, Qiu et al.)

• RGS10 inhibition in the knees exacerbates the severity of CIA manifestation. • RGS10 negatively regulates the NF-κB signaling pathway in CIA mouse model. • RGS10 regulation demonstrated a feedback mechanism of inflammation in macrophages. Rheumatoid arthritis (RA) is the most common inflammatory arthropathy, with evidence pointing to an immune-mediated etiology that propagates chronic inflammation. Although targeted immune therapeutics and aggressive treatment strategies have substantially improved, a complete understanding of the associated pathological mechanisms of the disease remains elusive. This study aimed at investigating whether regulator of G protein signaling 10 (RGS10) could affect rheumatoid arthritis (RA) pathology by regulating the immune response. A DBA/J1 mouse model of RA was established and evaluated for disease severity. RGS10 expression was inhibited by adeno-associated virus in vivo. Moreover, small interfering RNA was used to downregulate RGS10 expression in raw 264.7 cells in vitro. Results showed that RGS10 inhibition augmented RA severity, and attenuated the increase in expression of inflammatory factors. Furthermore, activated NF-κB signaling pathways were detected following RGS10 inhibition. These results revealed that RGS10 inhibition directly aggravated the RA pathological process by activating the NF-κB signaling pathway. Therefore, RGS10 is a promising novel therapeutic target for RA treatment with a potential clinical impact. [ABSTRACT FROM AUTHOR]

• RGS10 expression is significantly upregulated in FMF during attacks and remission, indicating a potential regulatory role in inflammatory processes. • Increased RGS10 expression in FMF is associated with decreased methylation, highlighting the epigenetic control of RGS proteins and suggesting therapeutic avenues for FMF management. • Enhanced RGS10 activity during both remission and attacks in FMF may offer therapeutic benefits by modulating inflammation, making it a promising target for disease management. • Elevated levels of specific histone modifications (H3K4me3, H3K9me2, and H3K14ac) are observed in FMF patients, highlighting significant epigenetic alterations that may contribute to disease pathogenesis. • RGS10 may initially enhance immune responses, genetic mutations and epigenetic changes in FMF may override this regulatory effect, leading to increased inflammation and clinical symptoms. Familial Mediterranean fever (FMF) is an autosomal recessive autoinflammatory disease characterized by recurring fever, erythema, joint pain, and abdominal discomfort during acute episodes. While FMF patients typically share MEFV gene mutations, they display varying clinical manifestations, suggesting the involvement of modifying genes, epigenetic mechanisms, or environmental factors. G protein regulator signal 10 (RGS10), a member of the RGS protein family, exhibits anti-inflammatory effects in autoinflammatory diseases. There are no studies on the role of plays in FMF pathogenesis or histone modification in FMF. This study aimed to shed light on the epigenetic regulation of FMF from several perspectives. The relationship between RGS10 DNA hypermethylation in FMF clinical parameters and the regulation of 22 histone modifications were examined in FMF attack patients and the control group. Sixty FMF (remission/attack) and thirty healthy individuals were included in the study. First, RNA was isolated from the blood of patients/controls, and the expression of RGS10 was examined. Then, DNA was isolated from the patients, and gene-specific hypermethylation was investigated using the bisulfite conversion method. Finally, histone extraction was performed for FMF patients and controls and 22 histone H3 modifications were determined. In addition, using ADEX bioinformatics tools, RGS10 expression and methylation profiles were detected in different autoinflammatory diseases. This study indicate that RGS10 expression decreased in attack-free/attack patients than control, attributed to DNA methylation. In addition, there were a positive correlation between FMF patients and attack, WBC, neutrophil, MCHC and MPV. Moreover, higher H3K4 me3, H3K9 me2, and H3K14ac levels were observed in patients with FMF attacks. This research also showed a consistent decrease in RGS10 expression in patients with SjS, SSc, and T1D compared with controls. I also obtained five prognosis-related CpGs (cg17527393, cg19653161, cg20445950, cg18938673 and cg13975098) of RGS10 in patients with SjS, RA, SSc, SLE and T1D. The present study provides insights into the complex relationship between RGS10 , epigenetic modifications, and immune responses in FMF. While RGS10 may initially enhance immune responses, genetic mutations and epigenetic changes associated with FMF acute episode may override this regulatory effect, resulting in increased inflammation and clinical symptoms. Moreover, our study revealed elevated levels of specific histone modifications in the context of FMF, suggesting significant epigenetic changes that could contribute to the disease pathogenesis. Understanding these associations opens new avenues for research and potential therapeutic interventions, potentially involving epigenetic therapies targeting histone modifications. [ABSTRACT FROM AUTHOR]

Ovarian cancer is one of the deadliest types of gynaecological cancers and more than half of the patients die within 5 years after diagnosis. Recurrence in advanced staged patients after chemotherapy is associated with increased chemoresistance, which results in poor prognosis. Regulator of G‐protein signalling 10 (RGS10) negatively regulates cell proliferation, migration and survival by attenuating G‐protein coupled‐receptors mediated signalling pathways. Recent studies have shown that loss of RGS10 expression is significantly associated with proliferation and cisplatin resistance in ovarian cancer cells. Significance of the study: In this study, we analysed differential RGS10 expression levels using public microarray datasets from clinical and in vitro ovarian cancer samples. We validated that cancer progression and chemotherapy exposure change RGS10 expression. We enriched our study to evaluate the relationship between chemoresistance and differential RGS10 expression against ovarian cancer potential chemotherapeutic agent, palbociclib. Results showed that palbociclib treatment reduced cell viability, despite significantly decreased RGS10 expression in chemoresistant cells. Overall, the results confirmed that cancer progression and chemoresistance are significantly associated with the down‐regulation of RGS10 while some chemotherapeutics seem to be beneficial in decreasing chemoresistance in ovarian cancer. [ABSTRACT FROM AUTHOR]

Objective: Excessive proliferation and migration of pulmonary arterial smooth muscle cell (PASMC) is a core event of pulmonary hypertension (PH). Regulators of G protein signaling 10 (RGS10) can regulate cellular proliferation and cardiopulmonary diseases. We demonstrate whether RGS10 also serves as a regulator of PH. Methods: PASMC was challenged by hypoxia to induce proliferation and migration. Adenovirus carrying Rgs10 gene (Ad-Rgs10) was used for external expression of Rgs10. Hypoxia/SU5416 or MCT was used to induce PH. Right ventricular systolic pressure (RVSP) and right ventricular hypertrophy index (RVHI) were used to validate the establishment of PH model. Results: RGS10 was downregulated in hypoxia-challenged PASMC. Ad-Rgs10 significantly suppressed proliferation and migration of PASMC after hypoxia stimulus, while silencing RGS10 showed contrary effect. Mechanistically, we observed that phosphorylation of S6 and 4E-Binding Protein 1 (4EBP1), the main downstream effectors of mammalian target of rapamycin complex 1 (mTORC1) as well as phosphorylation of AKT, the canonical upstream of mTORC1 in hypoxia-induced PASMC were negatively modulated by RGS10. Both recovering mTORC1 activity and restoring AKT activity abolished these effects of RGS10 on PASMC. More importantly, AKT activation also abolished the inhibitory role of RGS10 in mTORC1 activity in hypoxia-challenged PASMC. Finally, we also observed that overexpression of RGS10 in vivo ameliorated pulmonary vascular wall thickening and reducing RVSP and RVHI in mouse PH model. Conclusion: Our findings reveal the modulatory role of RGS10 in PASMC and PH via AKT/mTORC1 axis. Therefore, targeting RGS10 may serve as a novel potent method for the prevention against PH."

Inflammation in the aging brain increases risk for neurodegenerative disease. In humans, the regulator of G-protein signaling-10 (RGS10) locus has been associated with age-related maculopathy. Chronic peripheral administration of lipopolysaccharide in the RGS10-null mice induces nigral dopaminergic (DA) degeneration, suggesting that RGS10 modulates neuroimmune interactions and may influence susceptibility to neurodegeneration. Because age is the strongest risk factor for neurodegenerative disease, we assessed whether RGS10 expression changes with age and whether aged RGS10-null mice have altered immune cell profiles. Loss of RGS10 in aged mice does not alter the regulation of nigral DA neurons but does alter B-cell, monocyte, microglial, and CD4+ T-cell populations and inflammatory cytokine levels in the cerebrospinal fluid. These results suggest that loss of RGS10 is associated with an age-dependent dysregulation of peripheral and central immune cells rather than dysregulation of DA neuron function. [ABSTRACT FROM AUTHOR]

Colorectal cancer is known as the third most common cancer in both women and men. Genetic and epigenetic changes are major players contributing to colorectal carcinogenesis. Regulator of G-protein signaling 10 (RGS10) is a member of the RGS proteins, which negatively regulate several signaling pathways including cell survival and proliferation. We and others have previously shown that RGS10 expression is modulated by epigenetic modifications in ovarian cancer and suppression of RGS10 partially contributes to chemoresistance. Here, we further analyzed the roles and regulation of RGS10 in colon adenocarcinoma (COAD), using broad bioinformatics tools. We analyzed the expression profiles, promoter methylation state, prognostic value and effect of a hypomethylating agent on RGS10 expression. Results showed that RGS10 expression is higher in normal colon tissues than in tumor tissues. In addition, there is a negative correlation between DNA methylation and RGS10 transcript expression. We also observed that gene expression and promoter methylation of RGS10 in colorectal carcinoma patients were differently expressed depending on the tumor stage and microsatellite stability. DNA methylation was significantly increased in 18 probes of RGS10, which belongs to the high-risk group in COAD. In addition, pharmacological inhibition of DNA methyltransferase with decitabine reduced the six CpGsite-specific RGS10 hypermethylation in COAD. We also experimentally confirmed that RGS10 promoter activity was inhibited by treatment with decitabine in the HT-29 colorectal cell line. We further showed that decitabine treatment increases the RGS10 transcript expression in three different colorectal carcinoma cell lines. These results suggest that RGS10 expression is suppressed in the development of colorectal cancer and inhibition of DNA methylation may contribute to increasing overall survival rates of COAD patients. [ABSTRACT FROM AUTHOR]

Regulator of G protein signaling 10 (RGS10) belongs to the superfamily of RGS proteins, defined by the presence of a conserved RGS domain that canonically binds and deactivates heterotrimeric G-proteins. RGS proteins act as GTPase activating proteins (GAPs), which accelerate GTP hydrolysis on the G-protein α subunits and result in termination of signaling pathways downstream of G protein-coupled receptors. RGS10 is the smallest protein of the D/R12 subfamily and selectively interacts with Gαi proteins. It is widely expressed in many cells and tissues, with the highest expression found in the brain and immune cells. RGS10 expression is transcriptionally regulated via epigenetic mechanisms. Although RGS10 lacks multiple of the defined regulatory domains found in other RGS proteins, RGS10 contains post-translational modification sites regulating its expression, localization, and function. Additionally, RGS10 is a critical protein in the regulation of physiological processes in multiple cells, where dysregulation of its expression has been implicated in various diseases including Parkinson's disease, multiple sclerosis, osteopetrosis, chemoresistant ovarian cancer and cardiac hypertrophy. This review summarizes RGS10 features and its regulatory mechanisms, and discusses the known functions of RGS10 in cellular physiology and pathogenesis of several diseases. • RGS10 is dysregulated in response to multiple stimuli and various disease models. • Epigenetic and post-translational mechanisms regulate RGS10 expression and function. • RGS10 has emerged functions in cellular physiology and pathology. • Stabilizing RGS10 expression represents a promising therapeutic strategy. [ABSTRACT FROM AUTHOR]

Regulator of G protein signaling (RGS) proteins interact with activated Gα subunits via their RGS domains and accelerate the hydrolysis of GTP. Although the R4 subfamily of RGS proteins generally accepts both Gαi/o and Gαq/11 subunits as substrates, the R7 and R12 subfamilies select against Gαq/11. In contrast, only one RGS protein, RGS2, is known to be selective for Gαq/11. The molecular basis for this selectivity is not clear. Previously, the crystal structure of RGS2 in complex with Gαq revealed a non-canonical interaction that could be due to interfacial differences imposed by RGS2, the Gα subunit, or both. To resolve this ambiguity, the 2.6 Å crystal structure of RGS8, an R4 subfamily member, was determined in complex with Gαq. RGS8 adopts the same pose on Gαq as it does when bound to Gαi3, indicating that the non-canonical interaction of RGS2 with Gαq is due to unique features of RGS2. Based on the RGS8-Gαq structure, residues in RGS8 that contact a unique α-helical domain loop of Gαq were converted to those typically found in R12 subfamily members, and the reverse substitutions were introduced into RGS10, an R12 subfamily member. Although these substitutions perturbed their ability to stimulate GTP hydrolysis, they did not reverse selectivity. Instead, selectivity for Gαq seems more likely determined by whether strong contacts can be maintained between α6 of the RGS domain and Switch III of Gαq, regions of high sequence and conformational diversity in both protein families., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)