ISGylation of DRP1 closely balances other post-translational modifications to mediate mitochondrial fission

• Published in: Cell death & disease Vol. 15; no. 3; pp. 184 - 17
• Main Authors: Das, Palamou, Chakrabarti, Oishee
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 02-03-2024; Springer Nature B.V; Nature Publishing Group
• Subjects: 13/106; 13/109; 14/19; 38/70; 631/80/458/582; 631/80/474/1768; 64/110; Alzheimer's disease; Antibodies; Biochemistry; Biomedical and Life Sciences; Cell Biology; Cell Culture; Dynamin; Dynamins - genetics; Dynamins - metabolism; Filamentation; Immunology; Life Sciences; Mitochondria; Mitochondria - metabolism; Mitochondrial DNA; Mitochondrial Dynamics - physiology; Mitochondrial Proteins - genetics; Mitochondrial Proteins - metabolism; Neurodegenerative diseases; Phosphorylation; Post-translation; Protein Processing, Post-Translational; Proteins; RNA, Viral; Severe acute respiratory syndrome coronavirus 2; Translation; Ubiquitin-protein ligase
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-024-06543-7

Dynamin related protein 1 (DRP1), a pivotal mitochondrial fission protein, is post-translationally modified by multiple mechanisms. Here we identify a new post-translational modification of DRP1 by the ubiquitin-like protein, interferon-stimulated gene 15 (ISG15). DRP1 ISGylation is mediated by ISG15 E3 ligase, HERC5; this promotes mitochondrial fission. DeISGylation of DRP1 however leads to hyperfusion. Heterologous expression of SARS-CoV2 PLpro, a deISGylating enzyme, results in similar mitochondrial filamentation, significant decrease in total DRP1 protein levels and efflux of mtDNA. We report that deISGylated DRP1 gets ubiquitylated and degraded by TRIM25, instead of PARKIN and MITOL. While the cytosolic pool of DRP1 is primarily ISGylated, both mitochondrial and cytosolic fractions may be ubiquitylated. It is known that phosphorylation of DRP1 at S616 residue regulates its mitochondrial localisation; we show that ISGylation of phospho-DRP1 (S616) renders fission competence at mitochondria. This is significant because DRP1 ISGylation affects its functionality and mitochondrial dynamics in Alzheimer’s disease pathophysiology.