Elucidating the molecular basis of necroptosis

The National Institute of General Medical Sciences awarded the University of California, Berkeley $329,491 under the Biomedical Research and Research Training program (CFDA 93.859) on August 1, 2026, to elucidate the molecular basis of necroptosis through a five-year project extending to May 31, 2031.

The funded research investigates the ZBP1-RIPK3-MLKL necroptosis pathway, specifically how ZBP1 transitions from inactive to assembled states to engage RIPK3, how MLKL undergoes conformational changes to form membrane-permeabilizing pores, and how necroptotic protein homologs preserve or diverge across species. The project will establish molecular mechanisms of regulated cell death and provide a unifying framework across apoptosis, pyroptosis, and necroptosis. Dysregulated necroptosis contributes to dermatitis, inflammatory bowel disease, and neurodegeneration; understanding this pathway may inform interventions in these disease states.

Performance takes place at Berkeley, California. The award is structured as a Project Grant, providing five years of funding stability and flexibility under the NIGMS MIRA (Maximizing Investigators' Research Award) program, which the Institute prioritizes over traditional R01 awards to support ambitious yet feasible research directions.

Abstract

Regulated cell death represents a fundamental principle of life, shaping diverse physiological and pathological processes. Scientists have identified more than a dozen forms of regulated cell death, each with distinct molecular machinery and biological functions. While studies of apoptosis and pyroptosis have achieved extraordinary mechanistic clarity, our understanding of the molecular basis of necroptosis remains relatively limited. Necroptosis can proceed through multiple pathways, including the ZBP1-RIPK3-mlkl pathway that forms the focus of our R35 mira project. In this pathway, ZBP1 (sensor) detects nucleic acids (ligand) in the left-handed z conformation, which can arise exogenously during viral infection or endogenously from supercoiled or repetitive genomic regions. Upon ligand recognition, ZBP1 activates RIPK3 (transducer), which then activates mlkl (effector) by phosphorylation. Activated mlkl inserts into the plasma membrane and oligomerizes into pores, driving necroptotic cell lysis and fueling inflammation. Dysregulated necroptosis contributes to multiple pathologies, including dermatitis, inflammatory bowel disease, and neurodegeneration. In this project, we will elucidate the molecular basis of necroptosis by defining how ZBP1 transitions from APO to assembled states to engage RIPK3, how mlkl undergoes conformational changes to form membrane-permeabilizing pores, and how necroptotic protein homologs across species preserve or diverge from these mechanisms during evolution. Pursuing these directions will not only elevate our mechanistic understanding of necroptosis and its broad roles in health and disease, but also, together with existing knowledge of apoptosis and pyroptosis, provide a unifying framework for the general principles of regulated cell death. The R35 mira award enables US to pursue this ambitious yet feasible vision by providing five years of stability and flexibility, allowing US to take educated risks, obtain early results, and set the stage for a long-term integrative research program that bridges different forms of cell death across the tree of life.