The complex interplay between ULK1 and protein phosphatases in autophagy regulation. Issue 2 (1st February 2022)

• Record Type: Journal Article
• Authors: Siva Sankar, Devanarayanan; Hu, Zehan; Dengjel, Joern
• Is Part Of: Autophagy. Volume 18:Issue 2(2022)
• Page Start: 455
• Page End: 456
• Publication Date: 2022-02-01
• Subjects: Feedback -- in vitro kinase assay -- kinase -- phosphatase -- phosphoproteomics -- phosphorylation -- striatin -- STRIPAK -- STRN -- ULK1; Autophagic vacuoles -- Periodicals; Apoptosis -- Periodicals; Cell death -- Periodicals; Lysosomes -- Periodicals; Degeneration (Pathology) -- Periodicals; Autophagy -- Periodicals; Cell Death -- Periodicals; Lysosomes -- Periodicals; Periodicals; 571.936
• DOI: 10.1080/15548627.2021.2002546
• Languages: English
• ISSNs: 1554-8627

Abstract

ABSTRACT: ULK1 kinase is the gatekeeper of canonical macroautophagy (hereafter referred to as autophagy) phosphorylating an array of substrates critical for autophagosome biogenesis. To uncover if ULK1 has broader functions also regulating subsequent steps of autophagosome turnover, i.e., maturation, lysosomal fusion, and degradation, we performed a set of unbiased phosphoproteomic experiments employing mouse and human cells in combination with genetic and environmental perturbations. We characterized more than 1, 000 potential ULK1 target sites of which many affect proteins known to be involved in all phases of the autophagosome life cycle. To better understand which of these 1, 000 phosphosites were directly phosphorylated by ULK1, in contrast to downstream kinases being activated or phosphatases being inhibited by ULK1, we developed a proteome-scale in vitro kinase assay and characterized 187 phosphosites on 157 proteins as bona fide ULK1 target sites. Interestingly, our results highlight an intricate crosstalk between ULK1 and protein phosphatases. Focusing on STRN (striatin), a regulatory subunit of PPP2/PP2A (protein phosphatase 2), we identified a positive feedback loop linked to ULK1 and promoting autophagy.