Pellino 3 E3 ligase promotes starvation-induced autophagy to prevent hepatic steatosis.
| Title: | Pellino 3 E3 ligase promotes starvation-induced autophagy to prevent hepatic steatosis. |
|---|---|
| Authors: | Kolapalli SP; Cellular Homeostasis and Recycling, Danish Cancer Institute, DK-2100 Copenhagen, Denmark.; Beese CJ; Cellular Homeostasis and Recycling, Danish Cancer Institute, DK-2100 Copenhagen, Denmark.; Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.; Reid SE; Cellular Homeostasis and Recycling, Danish Cancer Institute, DK-2100 Copenhagen, Denmark.; Brynjólfsdóttir SH; Cellular Homeostasis and Recycling, Danish Cancer Institute, DK-2100 Copenhagen, Denmark.; Jørgensen MH; Cellular Homeostasis and Recycling, Danish Cancer Institute, DK-2100 Copenhagen, Denmark.; Jain A; Center for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Cuenco J; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200 Copenhagen, Denmark.; Lewinska M; Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.; Gubra, DK-2970 Hørsholm, Denmark.; Abdul-Al A; Cellular Homeostasis and Recycling, Danish Cancer Institute, DK-2100 Copenhagen, Denmark.; López AR; Cellular Homeostasis and Recycling, Danish Cancer Institute, DK-2100 Copenhagen, Denmark.; Jäättelä M; Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Institute, DK-2100 Copenhagen, Denmark.; Department of Cellular and Molecular Medicine, Faculty of Health Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.; Sakamoto K; Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, DK-2200 Copenhagen, Denmark.; Andersen JB; Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.; Maeda K; Cell Death and Metabolism, Center for Autophagy, Recycling and Disease, Danish Cancer Institute, DK-2100 Copenhagen, Denmark.; Rusten TE; Center for Cancer Cell Reprogramming, Faculty of Medicine, University of Oslo, Oslo, Norway.; Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.; Lund AH; Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark.; Frankel LB; Cellular Homeostasis and Recycling, Danish Cancer Institute, DK-2100 Copenhagen, Denmark.; Biotech Research and Innovation Centre, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark. |
| Source: | Science advances [Sci Adv] 2025 Jan 17; Vol. 11 (3), pp. eadr2450. Date of Electronic Publication: 2025 Jan 17. |
| Publication Type: | Journal Article |
| Language: | English |
| Journal Info: | Publisher: American Association for the Advancement of Science Country of Publication: United States NLM ID: 101653440 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 2375-2548 (Electronic) Linking ISSN: 23752548 NLM ISO Abbreviation: Sci Adv Subsets: MEDLINE |
| Imprint Name(s): | Original Publication: Washington, DC : American Association for the Advancement of Science, [2015]- |
| MeSH Terms: | Ubiquitin-Protein Ligases*/metabolism ; Ubiquitin-Protein Ligases*/genetics ; Fatty Liver*/metabolism ; Fatty Liver*/pathology ; Fatty Liver*/prevention & control ; Fatty Liver*/genetics ; Fatty Liver*/etiology ; Starvation*/metabolism ; Autophagy*; Autophagy-Related Protein-1 Homolog/metabolism ; Autophagy-Related Protein-1 Homolog/genetics ; Liver/metabolism ; Liver/pathology ; Autophagy-Related Protein 8 Family/metabolism ; Humans ; Animals ; Mice ; Ubiquitination ; Mice, Knockout ; Intracellular Signaling Peptides and Proteins |
| Abstract: | Nutrient deprivation is a major trigger of autophagy, a conserved quality control and recycling process essential for cellular and tissue homeostasis. In a high-content image-based screen of the human ubiquitome, we here identify the E3 ligase Pellino 3 (PELI3) as a crucial regulator of starvation-induced autophagy. Mechanistically, PELI3 localizes to autophagic membranes, where it interacts with the ATG8 proteins through an LC3-interacting region (LIR). This facilitates PELI3-mediated ubiquitination of ULK1, driving ULK1's subsequent proteasomal degradation. PELI3 depletion leads to an aberrant accumulation and mislocalization of ULK1 and disrupts the early steps of autophagosome formation. Genetic deletion of Peli3 in mice impairs fasting-induced autophagy in the liver and enhances starvation-induced hepatic steatosis by reducing autophagy-mediated clearance of lipid droplets. Notably, PELI3 expression is decreased in the livers of patients with metabolic dysfunction-associated steatotic liver disease (MASLD), suggesting its role in hepatic steatosis development in humans. The findings suggest that PELI3-mediated control of autophagy plays a protective role in liver health. |
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| Substance Nomenclature: | EC 2.3.2.27 (Ubiquitin-Protein Ligases); EC 2.7.11.1 (Autophagy-Related Protein-1 Homolog); 0 (Autophagy-Related Protein 8 Family); EC 2.7.11.1 (ULK1 protein, human); 0 (Intracellular Signaling Peptides and Proteins) |
| Entry Date(s): | Date Created: 20250117 Date Completed: 20250501 Latest Revision: 20260127 |
| Update Code: | 20260130 |
| PubMed Central ID: | PMC11740972 |
| DOI: | 10.1126/sciadv.adr2450 |
| PMID: | 39823344 |
| Database: | MEDLINE |
Journal Article