The major goal of the Perissi’s laboratory is to investigate the transcriptional and non-transcriptional functions of various components of the NCoR/SMRT corepressor complex and to dissect, both in vitro and in vivo, in tissue-specific mouse models, how the different components of this complex contribute to broadly regulate the cellular responses to external stimuli or to changes in bioenergetics needs. By understanding how cells physiologically respond to a number of stimuli by modulating hormonal, metabolic and inflammatory pathways we hope to help clarifying what happens when the same pathways are disrupted under pathological conditions.
Our most recent work has focused on GPS2, a component of the NCoR/SMRT corepressor complex, and the mechanism by which this protein serves to inhibit the pro-inflammatory TNFα pathway and prevent its unstimulated activation in different cell types including adipocytes, macrophages and B cells. In trying to dissect the molecular mechanism of GPS2 actions, we unexpectedly uncovered a critical non-transcriptional role for GPS2 in regulating the activation of JNK in the cytoplasm and keeping the lid on a pro-inflammatory gene program in the nucleus. This non-transcriptional function of GPS2 complements its repressor activity as part of the NCoR/SMRT complex and is based on its ability to modulate the activation of the TNFR signaling pathway via inhibition of TRAF2/CIAP1/Ubc13 enzymatic activity. Overall this work contributes to define GPS2 as an important regulator of metabolic organs and has broad implications for understanding the role of uncontrolled inflammatory responses in the development of disease states, including cancer and diabetes.
Ongoing projects aim at: i) dissect the effects of modulating GPS2 expression in vivo in the adipose tissue; ii) determine GPS2 role in the regulation of K63 ubiquitin chain formation within inflammatory responses regulated by Toll-like receptors and TNFalpha in macrophages and B-cells; iii) dissect the molecular mechanism of GPS2 role in nuclear receptor-mediated transcriptional regulation in differentiating and mature adipocytes; iv) understand how GPS2 subcellular localization and specific functions are regulated by post-translational modifications.
Our research efforts are possible thanks to generous support from:
NIH/NIDDK, Boston Nutrition and Obesity Center (BNORC), Joslin Diabetes Center, Grunebauam Cancer Foundation and Peter Paul Career Development Professorship.