G protein signaling, RGS proteins, proteasomal degradation, drug discovery

G protein-coupled receptors (GPCRs) represent the largest family of receptors and are important drug targets with 40-60% of currently FDA approved drugs targeting the receptors themselves or downstream mechanisms. One important regulatory mechanism of G protein signaling is mediated through a family of GTPase accelerating proteins, Regulator of G protein Signaling (RGS) proteins. RGS proteins modulate GPCR signaling by binding to and accelerating GTP hydrolysis on active Gα subunits of heterotrimeric G proteins. This results in attenuation of duration and amplitude of GPCR signaling. The majority of the more than 20 RGS proteins identified to date also possess additional functions not related to their canonical effect on G proteins. In the past 20 years, RGS proteins have emerged as novel drug targets in numerous disease states, such as hypertension, cancer and Parkinson disease among others. RGS proteins are tightly regulated through transcriptional, epigenetic and posttranslational mechanisms, such as degradation through the ubiquitin-proteasomal pathway. Furthermore, expression of RGS proteins is often altered during pathogenesis, causing dysregulation in GPCR signaling, that can cause or worsen the disease. Thus, the work in the Sjogren lab is focused on two central questions; 1) To understand the mechanisms by which levels and function of RGS proteins are regulated and; 2) How the knowledge of these mechanisms can be applied in drug discovery.

Two main projects are currently ongoing in the Sjogren lab, concerning RGS2 and RGS10. RGS2 is rapidly degraded through the ubiquitin-proteasomal pathway. In this essential system, a protein is targeted for degradation through the enzymatic coupling of a chain of ubiquitin molecules that serves as a recognition signal for the proteasome. Over 600 E3 ligases serve as substrate-recognizing components with great selectivity towards different proteins. Through high-throughput siRNA screening we identified a novel multiprotein E3 ligase responsible for RGS2 protein degradation. Current work aims to dissect the precise molecular mechanisms and interactions within this complex to determine what drives RGS2 protein degradation, using biochemical, structural and cell based systems. Another angle of this project is to develop a high-throughput assay to screen for novel inhibitors of RGS2 targeting by this E3 ligase.

RGS10 is heavily regulated through epigenetic mechanisms and has been implicated as a key regulator of neuroinflammation. This project aims to develop a high-throughput screening assay to be used for small molecule and siRNA screening for novel modulators of RGS10 in microglia. Through this work the lab aims to not only identify molecules that could be developed into novel therapeutics, but also unveil mechanism that regulate RGS10 expression in microglia.

https://www.mcmp.purdue.edu/faculty; https://www.mcmp.purdue.edu/faculty/jsjogren