Our laboratory investigates (1) cell-fate decisions—life or death—and (2) how cells behave under the threat of death and how they influence the surrounding environment. By dissecting these processes, we aim to clarify tissue homeostasis and the pathogenesis of inflammatory diseases and cancer, ultimately developing new therapies. We integrate a wide range of approaches including biochemistry, molecular and cell biology, immunology, genetic engineering, and genetically modified mouse models to achive our goals.
1. Molecular mechanisms and pathophysiological roles of necroptosis
Necrosis is defined by plasma-membrane rupture, which releases intracellular immunostimulatory molecules and provokes inflammation. Once considered unregulated, necrosis is now known to arise via defined pathways, establishing the concept of regulated necrosis.
Necroptosis, a prototypical regulated necrosis, is triggered by cytokines and pathogen-derived cues and contributes to various inflammatory diseases such as neurodegeneration, inflammatory bowel disease, and ischemia–reperfusion injury. Upon induction, stimulus-dependent oligomerization and activation of the cytosolic kinase RIPK3 via adaptor proteins such as RIPK1 drive phosphorylation of the membrane-disrupting effector MLKL, culminating in plasma membrane rupture.
We have long investigated the regulation of RIPK1, RIPK3, and MLKL, and their roles in inflammation and cancer. Representative work includes:
- Non-necroptotic, pro-inflammatory functions of RIPK3 (Cell Rep 2017; J Immunol 2015; Immunity 2014)
- Necroptosis in cancer (J Biol Chem 2016; Cell Death Dis 2015)
- pH-dependent regulation and homeostatic immune functions of RIPK1 (Sci Signal 2020; Mucosal Immunol 2022)
Current goals: (i) define the intracellular structure/dynamics and regulation of the amyloid-like RIPK3 oligomer (“necrosome”), and (ii) delineate the precise mechanism of MLKL-mediated membrane injury and rupture.
2. Evolutionary perspectives on regulated necrosis
Multiple genetically encoded death programs (apoptosis, necroptosis, pyroptosis, etc.) raise fundamental questions about when and how these machineries arose. We are tracing the evolutionary origin and molecular evolution of the RIPK3–MLKL necroptotic core module.
3. Intracellular responses to plasma-membrane injury and disease relevance
The plasma membrane sustains injuries of varying severity under physiological and pathological conditions. Minor lesions are rapidly repaired, but insults that exceed repair capacity or occur when repair fails lead to persistent damage and cellular dysfunction. When damage crosses a critical threshold, membrane rupture triggers necrosis. We are defining how cells sense and respond to membrane injury and how these responses shape disease processes.
4. Leveraging cell-death machinery for cancer therapy
Immune checkpoint inhibitors are now central to cancer therapy, yet some of patients do not benefit. One of the reasons is because tumors acquire resistance to cell death at the final effector step of immune killing. Cytotoxic T cells and CAR-T cells express death ligands (TRAIL and Fas ligand) that engage receptors on cancer cells to trigger death, but many cancers resist this pathway. We have studied the regulation of death ligand–induced tumor cell death and identified glycan-mediated control and a small molecule that sensitizes cancer cells (Oncogene 2022; Int J Mol Sci 2022; J Biol Chem 2011; Gastroenterology 2009). Our goal is to develop strategies that enhance the efficacy of immunotherapy.