PPP1R3G and transplanted renal graft function - kidney transplantation (KTX) is a life-saving procedure for patients with end-stage kidney disease

The National Institute of Diabetes and Digestive and Kidney Diseases awarded the University of South Florida $736,882 on August 20, 2026, under the Diabetes, Digestive, and Kidney Diseases Extramural Research program (CFDA 93.847) to investigate the role of protein phosphatase 1 regulatory subunit 3G (PPP1R3G) in ischemia-reperfusion injury during kidney transplantation.

The research focuses on understanding how PPP1R3G regulates receptor-interacting protein kinase 1 (RIPK1)-dependent cell death pathways in transplanted kidneys. The project will test the hypothesis that PPP1R3G activates apoptosis and necroptosis by recruiting protein phosphatase 1 and regulatory proteins to remove inhibitory modifications from RIPK1, with the goal of identifying peptide inhibitors that could mitigate ischemia-reperfusion-induced graft injury and improve long-term kidney graft function. This work addresses a critical gap in understanding cell death mechanisms central to delayed graft function and transplant rejection, particularly in marginal donor kidneys that experience multiple ischemic episodes.

Performance occurs in Tampa, Florida. The award period runs through May 31, 2030.

However, transplanted organs often encounter multiple episodes of ischemia and ischemia-reperfusion injury (IRI), especially for marginal donors, posing a significant risk to the long-term survival of transplanted kidneys. Death of renal cells is central to the pathophysiology of graft injury, delayed graft function and transplant rejection. Many of these conditions can be characterized as disorders involving cell count and inflammation. Therefore, a better understanding of the pathophysiological mechanisms contributing to cell death, along with identifying specific targets for preventing or treating IRI during KTX, is critically important and urgently needed to improve long-term survival of renal transplants. Receptor-interacting protein kinase 1 (RIPK1) is a crucial regulator of inflammation and cell death. RIPK1 activity is intricately controlled by extensive phosphorylation and ubiquitination. However, the mechanisms governing the dephosphorylation or deubiquitination of RIPK1, which is responsible for activating its kinase function and promoting cell death, remain poorly understood. Protein phosphatase 1 regulatory subunit 3G (PPP1R3G) is a regulatory subunit of protein phosphatase 1 (PP1) and has been demonstrated to be involved in the regulation of glucose homeostasis and hepatic glycogenesis as well as ripk autophosphorylation. However, the role of PPP1R3G in RIPK1-dependent cell death in KTX remains unexplored, which is the focus of the present proposal. In this proposal, we will test the novel hypothesis that PPP1R3G activates apoptosis and necroptosis by recruiting PP1Γ and USP14 to sequentially remove inhibitory phosphorylation sites from RIPK1. Deletion of PPPR1R3G mitigates IR-induced graft injury and improves kidney graft function. Peptide inhibitors disrupting the interaction between PPP1R3G and PP1Γ will effectively prevent RIPK1-dependent cell death and transplanted kidney graft injury. The innovative concept of inhibiting PPP1R3G to reduce IRI during transplantation and improve kidney graft function will greatly advance our understanding of PPP1R3G's role in tubular apoptosis and necroptosis. We will test novel peptidomimetics that disrupt the PPP1R3G/PP1Γ interaction to prevent tubular cell death in KTX. Successfully completing this proposal will offer new molecular insights into cell death pathways, identify potential drug candidates, and pave the way for novel therapeutic approaches to kidney graft injury and expand the donor pool.