Mechanisms of apoptosis in metazoan cells

As in a company restructure, a body remodeling itself during growth must not only recruit, by cell division and specialization, but also retrench, by killing off redundant cells. In adult animals too, normal and pathogenic processes can lead to an overabundance of cells that demands judicious pruning. Intriguingly, all doomed cells basically die by their own hands, undergoing suicide via co-ordinated, multi-step programs - apoptosis. Early work showed that the terminal stages of apoptosis are amazingly well conserved throughout evolution, from worms to humans. For every cell the suicidal tendency is actually an ever-threatening facet of its make-up. Minute-to-minute, each cell weighs up a multitude of internal and external signals, some favouring existence, others oblivion. Recently, the variety of potential signals, and also the differing signal-sensitivities of cells, have drawn attention to an unexplored multiplicity of pathways that converge upon the conserved core. We work on an ideal system to investigate these non-core pathways: human T cells. T cells serve in squads that target specific antigens, then self-destruct, yet manage to leave behind a few operatives primed to handle similar subsequent attacks. Working in unpredictable microenvironments, they respond flexibly to a wide repertoire of survive-or-suicide cues, as is also true for their different developmental stages. Using these adaptable, experimentally amenable cells our lab has helped to confirm that an unexpected group of cellular intermediates - reactive oxygen species - are critical for apoptosis in mature T cells. Our main goal now is to detail how these intermediates engage with previously characterized T cell termination pathways.

Recent Publications:

Perumalsamy LR., Nagala M., Bannerjee P and Sarin A [2009] A hierarchical cascade activated by non-canonical Notch signaling and the mTOR - Rictor complex regulates neglect-induced death in mammalian cells. Cell Death & Differentiation  16:879-889
Purushothanam D and Sarin A [2009] Cytokine-dependent regulation of NADPH oxidase activity and the consequences for activated T cell homeostasis Journal of Experimental Medicine 206:1515-1523
Perumalsamy LR., Nagala, M and Sarin A [2010] A Notch activated signaling cascade interacts with mitochondrial remodeling proteins to regulate cell survival Proceedings of the Natnl.  Acad. Sciences USA. (accepted).