The long-term goal of this project is to decipher the molecular pathways involved in regulating autophagy so that the process can be more precisely manipulated for the treatment of hematopoietic disorders and malignancies. Autophagy, the primary recycling pathway in cells, is largely responsible for the turnover of organelles, includin mitochondria, and long-lived or misfolded proteins. The ability of cells to induce appropriate levels of autophagy in response to various metabolic or proteotoxic stressors allows cells to survive and adapt to environmental challenges. Indeed, many tumors rely on autophagy for survival under adverse conditions. A recent study indicates that stabilization of Ulk1 protein (a key regulator of autophagy) in certain types of cancer is associated with a poor prognosis-perhaps as a consequence of enhanced ability to engage the autophagy machinery in response to stress. Thus, understanding the signaling pathways involved in regulating autophagy will not only provide insight into the role of autophagy in the maintenance of healthy cells and in disease, but should also reveal new targets for manipulating autophagy in the treatment of cancer. Ulk1 and Ulk2 are ubiquitously expressed mammalian homologues of Atg1, a well-characterized serine- threonine kinase that regulates both selective and non-selective autophagy in yeast. Ulk1 is required for amino acid starvation induced autophagy in cultured cells and for clearance of mitochondria in red blood cells and hepatocytes, and following depolarizing damage. Ulk2 has been implicated in autophagy;however, specific defects in Ulk2 knockout animals have not been reported. Rather, mice lacking both Ulk1 and Ulk2 show perinatal lethality similar to those lacking core non-redundant genes such as mAtg5 or mAtg7, suggesting that Ulk1 and Ulk2 share some overlapping functions in the regulation of autophagy. Given that deficiency of core autophagy genes is detrimental to organisms, identifying and characterizing differences in the regulation of Ulk1 and Ulk2 may reveal unique opportunities to selectively target one or the other protein, and more precisely manipulate autophagy in the treatment of cancer. Recent studies have demonstrated that while both Ulk1 and Ulk2 are substrates of the energy-sensing kinase AMPK, Ulk1 alone (not Ulk2) is a client of the Hsp90-Cdc37 chaperone complex whose activation and stability is sensitive to alterations in Hsp90 function. Despite the importance of both AMPK and Hsp90-Cdc37 in activating Ulk1 function and in maintaining cellular homeostasis, the way in which these players cooperate to integrate regulation of autophagy and mitochondrial turnover with the changing energy demands of the cell remains unclear. Since the primary phenotype associated with Ulk1-deficiency in vivo is a defect in the clearance of mitochondria during the terminal stages of erythroid maturation, we propose to examine the molecular basis and physiologic relevance of Ulk1 regulation by AMPK and Hsp90-Cdc37 in the context of erythroid maturation through a combination of biochemical, structural and cell biological approaches using both cell-based and in vivo models.
This proposal is focused on understanding the regulation of autophagy (self-eating), a cellular response to stress and starvation, which has been implicated in the pathogenesis of diseases, including neurodegeneration, diabetes, and cancer.
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|Joshi, A; Iyengar, R; Joo, J H et al. (2016) Nuclear ULK1 promotes cell death in response to oxidative stress through PARP1. Cell Death Differ 23:216-30|
|Lim, Junghyun; Lachenmayer, M Lenard; Wu, Shuai et al. (2015) Proteotoxic stress induces phosphorylation of p62/SQSTM1 by ULK1 to regulate selective autophagic clearance of protein aggregates. PLoS Genet 11:e1004987|
|Ness, Kirsten K; Armstrong, Gregory T; Kundu, Mondira et al. (2015) Frailty in childhood cancer survivors. Cancer 121:1540-7|
|Li-Harms, XiuJie; Milasta, Sandra; Lynch, John et al. (2015) Mito-protective autophagy is impaired in erythroid cells of aged mtDNA-mutator mice. Blood 125:162-74|
|Kanneganti, Thirumala-Devi; Kundu, Mondira; Green, Douglas R (2015) Innate immune recognition of mtDNA--an undercover signal? Cell Metab 21:793-4|
|Kundu, Mondira (2014) Too sweet for autophagy: hexokinase inhibition of mTORC1 activates autophagy. Mol Cell 53:517-8|
|Figueroa, Maria E; Chen, Shann-Ching; Andersson, Anna K et al. (2013) Integrated genetic and epigenetic analysis of childhood acute lymphoblastic leukemia. J Clin Invest 123:3099-111|
|Lupfer, Christopher; Thomas, Paul G; Anand, Paras K et al. (2013) Receptor interacting protein kinase 2-mediated mitophagy regulates inflammasome activation during virus infection. Nat Immunol 14:480-8|
|Kim, Nam Chul; Tresse, Emilie; Kolaitis, Regina-Maria et al. (2013) VCP is essential for mitochondrial quality control by PINK1/Parkin and this function is impaired by VCP mutations. Neuron 78:65-80|
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