The E3 ligase TRIM1 ubiquitinates LRRK2 and controls its localization, degradation, and toxicity

J Cell Biol. 2022 Apr 4;221(4):e202010065. doi: 10.1083/jcb.202010065. Epub 2022 Mar 10.


Missense mutations in leucine-rich repeat kinase 2 (LRRK2) are the most common cause of familial Parkinson's disease (PD); however, pathways regulating LRRK2 subcellular localization, function, and turnover are not fully defined. We performed quantitative mass spectrometry-based interactome studies to identify 48 novel LRRK2 interactors, including the microtubule-associated E3 ubiquitin ligase TRIM1 (tripartite motif family 1). TRIM1 recruits LRRK2 to the microtubule cytoskeleton for ubiquitination and proteasomal degradation by binding LRRK2911-919, a nine amino acid segment within a flexible interdomain region (LRRK2853-981), which we designate the "regulatory loop" (RL). Phosphorylation of LRRK2 Ser910/Ser935 within LRRK2 RL influences LRRK2's association with cytoplasmic 14-3-3 versus microtubule-bound TRIM1. Association with TRIM1 modulates LRRK2's interaction with Rab29 and prevents upregulation of LRRK2 kinase activity by Rab29 in an E3-ligase-dependent manner. Finally, TRIM1 rescues neurite outgrowth deficits caused by PD-driving mutant LRRK2 G2019S. Our data suggest that TRIM1 is a critical regulator of LRRK2, controlling its degradation, localization, binding partners, kinase activity, and cytotoxicity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Cytoskeleton
  • Humans
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2* / genetics
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2* / metabolism
  • Microtubule-Associated Proteins
  • Microtubules
  • Mutation
  • Parkinson Disease* / metabolism
  • Phosphorylation
  • Protein Serine-Threonine Kinases* / genetics
  • Transcription Factors
  • Tripartite Motif Proteins* / metabolism
  • Ubiquitin-Protein Ligases / genetics
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination
  • rab GTP-Binding Proteins / metabolism


  • MID2 protein, human
  • Microtubule-Associated Proteins
  • Rab29 protein, human
  • Transcription Factors
  • Tripartite Motif Proteins
  • Ubiquitin-Protein Ligases
  • LRRK2 protein, human
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2
  • Protein Serine-Threonine Kinases
  • rab GTP-Binding Proteins