Academic Background

Education:

The Role of Programmed Cell Death in Immune Functions and Diseases

Cell death plays an essential role in metazoan homeostasis.  Members of the tumor necrosis factor (TNF) and TNF receptor (TNFR) family are crucial regulators of cell death.  Our lab is interested in how cell death contributes to the induction of immune responses.  One of the ways by which cell death can modulate immune responses is through the induction of programmed necrosis.  Necrotic cell death is distinguished from apoptosis by extensive cell and organelle swelling, the early rupture of plasma membrane, and the lack of caspase activation.   The release of endogenous cellular adjuvants can cause inflammation and stimulate immune responses.   Our long-term goal is to understand the biochemical regulation of programmed necrosis and the role programmed necrosis plays in inflammation, virus infections, autoimmune diseases and cancers.

Current projects:

1. Molecular regulation of programmed necrosis

Using RNA interference, we have recently identified several kinases including RIP1 and RIP3 that critically regulate programmed necrosis.  We show that a pro-necrotic signaling complex containing RIP1 and RIP3 are critically required for the induction of programmed necrosis.  We are currently investigating how the assembly of this RIP1-RIP3 complex is regulated.  Moreover, we are interested in identifying the downstream substrates for the RIP1-RIP3 kinase complex, and the effector mechanism that causes necrotic cell injury.

2. Programmed necrosis in anti-viral immunity

One of the physiological situations in which necrosis plays an important role is during viral infections.  Using vaccinia virus infections in mice as models, we have demonstrated a critical role for RIP3-dependent programmed necrosis in virus-induced inflammation and innate immune responses.  We are currently examining whether programmed necrosis and the subsequent inflammation it causes may also impact the induction of adaptive immune responses.  In addition, we are evaluating the role of programmed necrosis in other virus infections. 

3. How do viruses inhibit host cell death?

Inhibition of host cell death is widely touted as an immune evasion strategy employed by viruses.  In support of this hypothesis, many viruses encode inhibitors against the host cell death machinery.  We have recently identified several classes of viral inhibitors that potently inhibits programmed necrosis.   One of the challenges in the future will be to identify the molecular mechanisms by which viral inhibitors modulate the pro-necrotic signaling pathway.

4. Regulation of TRAIL signaling in immune cells

TRAIL (TNF-related apoptosis inducing ligand) is a TNF-like cytokine with potent cytotoxicity against many tumor cells, but are generally non-toxic to normal cells.  Of the five identified TRAIL receptors, two are termed “decoys” due to their ability to negatively regulate the apoptotic function of other TRAIL receptors.  We have found that signaling by TRAIL is in part regulated at the level of assembly of “pre-ligand complexes” between death receptors and the decoy receptors.  Current and future efforts will focus on understanding how the assembly of different TRAIL receptor complexes regulates death and non-death signaling in immune cells and cancer cells.