Tumor Suppressor Localization and Function at the Peroxisome

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 DESCRIPTION (provided by applicant): Peroxisomes are autonomously replicating organelles, and a major source of ROS generation in the cell. In the previous funding period, we made two major discoveries that form the basis for this competitive renewal: 1) the DNA repair kinase ATM "moonlights" in the cytoplasm where it signals to the TSC tumor suppressor to repress mTORC1 signaling in response to ROS and 2) the TSC signaling node (TSC1, TSC2 and Rheb) is resident at the peroxisome, where it is activated in response to ROS generation by this organelle. These findings have led us to hypothesize that the peroxisome is an import site for functional interaction between the TSC and ATM tumor suppressors, and that this interaction plays a key role in maintaining peroxisomal homeostasis by regulating selective autophagy of peroxisome (pexophagy). We hypothesize that ATM localizes to the peroxisome, where it is activated by peroxisomal ROS and signals downstream to TSC2 to suppress mTORC1 (Aim 1). In addition to the TSC tumor suppressor, our Preliminary Data suggest the ATM kinase also phosphorylates PEX5 (and perhaps other) proteins resident at the peroxisome (Aim 2), targeting them for ubiquitination and recognition by autophagy adaptor proteins to recruit the autophagosome to the peroxisome and mediate pexophagy (Aim 3). Together, the studies proposed in this application would be the first to demonstrate ATM signaling at the peroxisome, and to define new functional site for interaction of the ATM and TSC tumor suppressors, with important implications for understanding the role of these tumor suppressors in peroxisome homeostasis and maintenance of cellular redox balance.