Atypical Ubiquitination and Parkinson's Disease

Int J Mol Sci. 2022 Mar 28;23(7):3705. doi: 10.3390/ijms23073705.

Abstract

Ubiquitination (the covalent attachment of ubiquitin molecules to target proteins) is one of the main post-translational modifications of proteins. Historically, the type of polyubiquitination, which involves K48 lysine residues of the monomeric ubiquitin, was the first studied type of ubiquitination. It usually targets proteins for their subsequent proteasomal degradation. All the other types of ubiquitination, including monoubiquitination; multi-monoubiquitination; and polyubiquitination involving lysine residues K6, K11, K27, K29, K33, and K63 and N-terminal methionine, were defined as atypical ubiquitination (AU). Good evidence now exists that AUs, participating in the regulation of various cellular processes, are crucial for the development of Parkinson's disease (PD). These AUs target various proteins involved in PD pathogenesis. The K6-, K27-, K29-, and K33-linked polyubiquitination of alpha-synuclein, the main component of Lewy bodies, and DJ-1 (another PD-associated protein) is involved in the formation of insoluble aggregates. Multifunctional protein kinase LRRK2 essential for PD is subjected to K63- and K27-linked ubiquitination. Mitophagy mediated by the ubiquitin ligase parkin is accompanied by K63-linked autoubiquitination of parkin itself and monoubiquitination and polyubiquitination of mitochondrial proteins with the formation of both classical K48-linked ubiquitin chains and atypical K6-, K11-, K27-, and K63-linked polyubiquitin chains. The ubiquitin-specific proteases USP30, USP33, USP8, and USP15, removing predominantly K6-, K11-, and K63-linked ubiquitin conjugates, antagonize parkin-mediated mitophagy.

Keywords: Parkinson’s disease; atypical ubiquitination; deubiquitinase inhibitors; ubiquitin–proteasome system.

Publication types

  • Review

MeSH terms

  • Humans
  • Lysine / metabolism
  • Mitochondrial Proteins / metabolism
  • Parkinson Disease* / metabolism
  • Thiolester Hydrolases / metabolism
  • Ubiquitin / metabolism
  • Ubiquitin Thiolesterase / metabolism
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitin-Specific Proteases / metabolism
  • Ubiquitination

Substances

  • Mitochondrial Proteins
  • Ubiquitin
  • Usp30 protein, human
  • Ubiquitin-Protein Ligases
  • Thiolester Hydrolases
  • USP15 protein, human
  • USP33 protein, human
  • Ubiquitin Thiolesterase
  • Ubiquitin-Specific Proteases
  • Lysine