Department of Paediatrics, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, Hong Kong, China.
J Leukoc Biol. 2022 Oct;112(4):785-797. doi: 10.1002/JLB.1MR0422-475R. Epub 2022 Jun 13.
G-protein-coupled receptors (GPCRs) are the largest and most diverse group of membrane receptors. They are involved in almost every physiologic process and consequently have a pivotal role in an extensive number of pathologies, including genetic, neurologic, and immune system disorders. Indeed, the vast array of GPCRs mechanisms have led to the development of a tremendous number of drug therapies and already account for about a third of marketed drugs. These receptors mediate their downstream signals primarily via G proteins. The regulators of G-protein signaling (RGS) proteins are now in the spotlight as the critical modulatory factors of active GTP-bound Gα subunits of heterotrimeric G proteins to fine-tune the biologic responses driven by the GPCRs. Also, they possess noncanonical functions by multiple mechanisms, such as protein-protein interactions. Essential roles and impacts of these RGS proteins have been revealed in physiology, including hematopoiesis and immunity, and pathologies, including asthma, cancers, and neurologic disorders. This review focuses on the largest subfamily of R4 RGS proteins and provides a brief overview of their structures and G-proteins selectivity. With particular interest, we explore and highlight, their expression in the hematopoietic system and the regulation in the engraftment of hematopoietic stem/progenitor cells (HSPCs). Distinct expression patterns of R4 RGS proteins in the hematopoietic system and their pivotal roles in stem cell trafficking pave the way for realizing new strategies for enhancing the clinical performance of hematopoietic stem cell transplantation. Finally, we discuss the exciting future trends in drug development by targeting RGS activity and expression with small molecules inhibitors and miRNA approaches.
G 蛋白偶联受体（GPCRs）是最大和最多样化的膜受体群体。它们参与几乎所有的生理过程，因此在许多病理学中起着关键作用，包括遗传、神经和免疫系统疾病。事实上，大量的 GPCR 机制导致了大量药物治疗方法的发展，这些药物已经占到了上市药物的约三分之一。这些受体主要通过 G 蛋白介导其下游信号。G 蛋白信号转导调节因子（RGS）蛋白作为异三聚体 G 蛋白活性 GTP 结合 Gα亚基的关键调节因子，现已成为焦点，可精细调节 GPCR 驱动的生物反应。此外，它们通过多种机制（如蛋白-蛋白相互作用）具有非典型功能。这些 RGS 蛋白在生理学中，包括造血和免疫，以及病理学中，包括哮喘、癌症和神经紊乱中，发挥着重要作用和影响。本综述重点介绍 R4 RGS 蛋白的最大亚家族，并简要概述其结构和 G 蛋白选择性。特别感兴趣的是，我们探讨并强调了它们在造血系统中的表达及其对造血干细胞/祖细胞（HSPCs）植入的调节作用。R4 RGS 蛋白在造血系统中的独特表达模式及其在干细胞迁移中的关键作用为实现增强造血干细胞移植临床性能的新策略铺平了道路。最后，我们讨论了通过小分子抑制剂和 miRNA 方法靶向 RGS 活性和表达进行药物开发的令人兴奋的未来趋势。
