Demeter, A. | bioRxiv Science

bioRxiv2023

AutophagyNet: High-resolution data source for the analysis of autophagy and its regulation

Autophagy is a highly-conserved catabolic process eliminating dysfunctional cellular components and invading pathogens. Autophagy malfunction contributes to disorders such as cancer, neurodegenerative and inflammatory diseases. Understanding autophagy regulation in health and disease has been the focus of the last decades. We previously provided an integrated database for autophagy research, the Autophagy Regulatory Network (ARN). For the last seven years, this resource has been used by thousands of users. Here, we present a new and upgraded resource, AutophagyNet. It builds on the previous database but contains major improvements to address user feedback and novel needs due to the advancement in omics data availability. AutophagyNet contains updated interaction curation and integration of over 280,000 experimentally verified interactions between core autophagy proteins and their protein, transcriptional and post-transcriptional regulators as well as their potential upstream pathway connections. AutophagyNet provides annotations for each core protein about their role: 1) in different types of autophagy (mitophagy, xenophagy, etc.); 2) in distinct stages of autophagy (initiation, elongation, termination, etc); 3) with subcellular and tissue-specific localization. These annotations can be used to filter the dataset, providing customizable download options tailored to the users needs. The resource is available in various file formats (e.g., CSV, BioPAX and PSI-MI), and data can be analyzed and visualized directly in Cytoscape. The multi-layered regulation of autophagy can be analyzed by combining AutophagyNet with tissue- or cell type-specific using (multi-)omics datasets (e.g. transcriptomic or proteomic data). The resource is publicly accessible at http://autophagynet.org.

bioinformatics↗

bioRxiv2020

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

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). Deletion of ULK1 is sufficient to interrupt autophagy, while ULK2 seems expendable. To understand the differences between ULK1 and ULK2, we compared the human ULK1 and ULK2 proteins and their regulation. Despite the high similarity in their enzymatic domain, we found that ULK1 and ULK2 have major differences in their post-translational and transcriptional regulators. We identified 18 ULK1-specific and 7 ULK2-specific protein motifs serving as different interaction interfaces. 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. For example, we found a condition-specific, opposite effect on apoptosis regulation for the two ULK proteins. Given the importance of autophagy in diseases such as inflammatory bowel disease and cancer, unravelling differences between ULK1 and ULK2 could lead to a better understanding of how autophagy is dysregulated in diseased conditions.

molecular biology↗