ULK1 and ULK2 are less redundant than previously thought:computational analysis uncovers distinct regulation and functions of these autophagy induction proteins

Demeter, Amanda, Romero-Mulero, Mari Carmen, Csabai, Luca, Ölbei, Márton, Sudhakar, Padhmanand, Haerty, Wilfried ORCID: https://orcid.org/0000-0003-0111-191X and Korcsmáros, Tamás (2020) ULK1 and ULK2 are less redundant than previously thought:computational analysis uncovers distinct regulation and functions of these autophagy induction proteins. Scientific Reports, 10 (1). ISSN 2045-2322

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Abstract

Macroautophagy, the degradation of cytoplasmic content by lysosomal fusion, is an evolutionary conserved process promoting homeostasis and intracellular defence. Macroautophagy is initiated primarily by a complex containing ULK1 or ULK2 (two paralogs of the yeast Atg1 protein). To understand the differences between ULK1 and ULK2, we compared the human ULK1 and ULK2 proteins and their regulation. Despite the similarity in their enzymatic domain, we found that ULK1 and ULK2 have major differences in their autophagy-related interactors and their post-translational and transcriptional regulators. We identified 18 ULK1-specific and 7 ULK2-specific protein motifs serving as different interaction interfaces. We found that interactors of ULK1 and ULK2 all have different tissue-specific expressions partially contributing to diverse and ULK-specific interaction networks in various tissues. We identified three ULK1-specific and one ULK2-specific transcription factor binding sites, and eight sites shared by the regulatory region of both genes. Importantly, we found that both their post-translational and transcriptional regulators are involved in distinct biological processes—suggesting separate functions for ULK1 and ULK2. Unravelling differences between ULK1 and ULK2 could lead to a better understanding of how ULK-type specific dysregulation affects autophagy and other cellular processes that have been implicated in diseases such as inflammatory bowel disease and cancer.

Item Type: Article
Additional Information: Funding Information: The authors are grateful for the helpful discussions to the past and present members and visitors of the Haerty and Korcsmaros groups. Molecular graphics and analyses performed with UCSF Chimera, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from NIH P41-GM103311. This work was supported by a fellowship to TK in computational biology at the Earlham Institute (Norwich, UK) in partnership with the Quadram Institute (Norwich, UK), and strategically supported by the Biotechnological and Biosciences Research Council, UK Grants (BB/J004529/1, BB/ P016774/1). AD, TK and WH were supported by a BBSRC Core Strategic Programme Grant (BB/CSP17270/1). TK and AD were also funded by a BBSRC ISP grant for Gut Microbes and Health BB/R012490/1 and its constituent project(s), BBS/E/F/000PR10353 and BBS/E/F/000PR10355. MCRM was funded by an Erasmus Traineeship Grant from the European Commission. MO was supported by the BBSRC Norwich Research Park Biosciences Doctoral Training Partnership (Grant BB/M011216/1). WH was supported by an MRC Award (MR/P026028/1). Publisher Copyright: © 2020, The Author(s).
Uncontrolled Keywords: general,sdg 3 - good health and well-being ,/dk/atira/pure/subjectarea/asjc/1000
Faculty \ School: Faculty of Science > School of Biological Sciences
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Depositing User: LivePure Connector
Date Deposited: 15 Sep 2022 14:30
Last Modified: 22 Sep 2022 19:33
URI: https://ueaeprints.uea.ac.uk/id/eprint/88314
DOI: 10.1038/s41598-020-67780-2

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