Efficient removal of damaged sub-cellular organelles via the autophagy-lysosome machinery is critical for maintaining cardiac myocyte viability in homeostasis and with ischemia-reperfusion (IR) injury. Emerging evidence implicates an essential role for innate immunity proteins as intracellular `damage sensors' to orchestrate their autophagic removal. One such protein, TRAF2 (Tumor necrosis factor Receptor-Associated Factor-2), activates cytoprotective signaling downstream of both TNF receptors to prevent IR-induced cardiomyocyte death. We have recently discovered a novel role for TRAF2 as an E3 ubiquitin ligase in autophagic removal of damaged mitochondria in cardiac myocytes. Mitochondrial damage triggers stabilization of PINK1, a serine-threonine kinase, on the outer mitochondrial membrane, which recruits PARKIN, an E3 ubiquitin ligase to ubiquitin- tag mitochondrial proteins for degradation. Whether PINK1 signaling also recruits TRAF2 to damaged mitochondria; and whether TRAF2, plays a non-redundant role vis--vis PARKIN in mitochondrial autophagy, in vivo, is not known. In parallel studies, we have also uncovered evidence for endoplasmic reticulum (ER) permeabilization under conditions of ER stress and in cardiac IR injury. ER damage activates IRE1?, an ER-localized serine-threonine kinase and RNAase, which interacts with TRAF2; and in-vitro studies indicate that IRE1?-TRAF2 signaling at the mitochondria associated membranes (MAM) orchestrates autophagy of damaged mitochondria and ER. In this proposal, we will test the hypothesis that TRAF2 signaling mediates selective autophagy of endoplasmic reticulum and mitochondria to regulate cardiac myocyte survival in homeostasis and under stress; under three specific aims.
In aim 1, we will determine the role of TRAF2 in cardiac myocyte survival in homeostasis and under stress.
In aim 2, we will examine the role of TRAF2 vis--vis PARKIN in mitochondrial autophagy in cardiac myocytes.
In aim 3, we will determine the role of IRE1?-TRAF2 signaling axis in ER-phagy in cardiac myocytes. These studies will elucidate the cellular basis for targeting TRAF2 as an innate immunity sensor that coordinates autophagic removal of damaged organelles at the mitochondria-ER interface (MAM) to enhance cardiomyocyte survival in myocardial infarction and prevent heart failure, a key mission of the NIH.
Heart failure, the most common cause of death in the United States, is triggered by myocardial infarction and coronary artery disease in the majority of cases. Activation of the innate immunity system, a first line of defense against injury; and autophagy, a process for removal of damaged intracellular material, are essential for cell survival under these conditions. This proposal critically examines the role of TRAF2, an innate immunity signaling protein, in removal of damaged essential organelles in the setting of ischemic injury to ensure heart muscle cell survival and develop strategies to salvage cardiac muscle and prevent heart failure.
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