TRIM22 facilitates autophagosome-lysosome fusion by mediating the association of GABARAPs and PLEKHM1

Autophagy. 2024 May;20(5):1098-1113. doi: 10.1080/15548627.2023.2287925. Epub 2023 Dec 7.

Abstract

Tripartite motif (TRIM) proteins are a large family of E3 ubiquitin ligases implicated in antiviral defense systems, tumorigenesis, and protein quality control. TRIM proteins contribute to protein quality control by regulating the ubiquitin-proteasome system, endoplasmic reticulum-associated degradation, and macroautophagy/autophagy. However, the detailed mechanisms through which various TRIM proteins regulate downstream events have not yet been fully elucidated. Herein, we identified a novel function of TRIM22 in the regulation of autophagy. TRIM22 promotes autophagosome-lysosome fusion by mediating the association of GABARAP family proteins with PLEKHM1, thereby inducing the autophagic clearance of protein aggregates, independent of its E3 ubiquitin ligase activity. Furthermore, a TRIM22 variant associated with early-onset familial Alzheimer disease interferes with autophagosome-lysosome fusion and autophagic clearance. These findings suggest TRIM22 as a critical autophagic regulator that orchestrates autophagosome-lysosome fusion by scaffolding autophagy-related proteins, thus representing a potential therapeutic target in neurodegenerative diseases.Abbreviations: AD: Alzheimer disease; ADAOO: AD age of onset; AICD: APP intracellular domain; APP: amyloid beta precursor protein; BSA: bovine serum albumin; cDNAs: complementary DNAs; CQ: chloroquine; CTF: carboxyl-terminal fragment; EBSS: Earle's balanced salt solution; GABARAP: GABA type A receptor-associated protein; GST: glutathione S-transferase; HA: hemagglutinin; HOPS: homotypic fusion and protein sorting; IFN: interferon; IL1A/IL-1α: interleukin 1 alpha; KO: knockout; MTORC1: mechanistic target of rapamycin kinase complex 1; NFKBIA/IκBα: NFKB inhibitor alpha; NFE2L2/NRF2: NFE2 like bZIP transcription factor; PBS: phosphate-buffered saline; PI3K: class I phosphoinositide 3-kinase; PLA: proximity ligation assay; PLEKHM1: pleckstrin homology and RUN domain containing M1; PSEN1: presenilin 1; SEM: standard errors of the means; SNAREs: soluble N-ethylmaleimide-sensitive factor attachment protein receptors; SNCA: synuclein alpha; SNP: single nucleotide polymorphism; TBS: tris-buffered saline; TNF/TNF-α: tumor necrosis factor; TRIM: tripartite motif; ULK1: unc-51 like autophagy activating kinase 1; WT: wild-type.

Keywords: Alzheimer disease; PLEKHM1; TRIM22; autophagosome-lysosome fusion; autophagy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing* / metabolism
  • Alzheimer Disease / genetics
  • Alzheimer Disease / metabolism
  • Alzheimer Disease / pathology
  • Animals
  • Apoptosis Regulatory Proteins / metabolism
  • Autophagosomes* / metabolism
  • Autophagy* / physiology
  • Autophagy-Related Proteins
  • HEK293 Cells
  • Humans
  • Lysosomes* / metabolism
  • Membrane Fusion*
  • Microtubule-Associated Proteins / metabolism
  • Minor Histocompatibility Antigens
  • Protein Binding
  • Repressor Proteins
  • Tripartite Motif Proteins* / genetics
  • Tripartite Motif Proteins* / metabolism

Substances

  • Tripartite Motif Proteins
  • Adaptor Proteins, Signal Transducing
  • PLEKHM1 protein, human
  • TRIM22 protein, human
  • GABARAP protein, human
  • Microtubule-Associated Proteins
  • Apoptosis Regulatory Proteins
  • Autophagy-Related Proteins
  • Repressor Proteins
  • Minor Histocompatibility Antigens

Grants and funding

This study was supported by grants from the National Research Foundation of Korea (NRF) funded by the Ministry of Science and ICT to J.C. (NRF-2019R1A5A2026045, NRF-2020R1A2C1010399) and to S.L. (NRF-2020R1A2C1101827, NRF-2021R1A5A2031612).