Regulation of autophagy by the protein complex centered around serine-threonine kinase Atg1 has become well-characterized as a response to nutrient deprivation. However, understanding of how of the Atg1 autophagy induction complex drives autophagy is incomplete. Furthermore, many varied stresses lead to induction of autophagy. While many of these stresses have been linked to canonical autophagy regulation through Atg1, some have been shown to induce autophagy even in its absence. How the autophagic machinery is engaged in the absence of Atg1 remains an open question. Here we describe the induction of autophagy in the absence of Atg1 by a previously uncharacterized Drosophila protein we have named "Another Drosophila Unc-51-like Kinase" (ADUK) after the family of kinases that include ADUK and Atg1. Overexpression of ADUK induces autophagy in WT animals or Atg1 mutants, and GFP-ADUK localizes in punctae at autophagosomes. Interestingly, autophagy induction by ADUK requires Atg1 binding partner Atg13, and, like Atg1, ADUK co-immunoprecipitates with Atg13. Co-expression of Atg1 complex member FIP200 with ADUK enhances autophagy induction and GFP-ADUK punctae formation. Surprisingly, co-expression of Atg13 inhibited both ADUK phenotypes. ADUK mutation results in a reduced post-eclosure lifespan, and inhibits autophagy in response to a complex stressor, DMSO, but not in response to the canonical autophagy stimulus of amino acid deprivation. We conclude that ADUK represents a novel regulator of autophagy, likely engaging the downstream autophagic machinery in a manner similar to Atg1. As an Atg1-independent inducer, ADUK represents a new potential access point for autophagy regulation by non-nutrient stresses.
University of Minnesota Ph.D. dissertation. August 2015. Major: Molecular, Cellular, Developmental Biology and Genetics. Advisor: Thomas Neufeld. 1 computer file (PDF); v, 61 pages.
Regulation of autophagy by the Unc51 family kinases Atg1 and ADUK in Drosophila melanogaster.
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