Structure, dynamics and functions of UBQLNs: at the crossroads of protein quality control machinery

Biochem J. 2020 Sep 30;477(18):3471-3497. doi: 10.1042/BCJ20190497.

Abstract

Cells rely on protein homeostasis to maintain proper biological functions. Dysregulation of protein homeostasis contributes to the pathogenesis of many neurodegenerative diseases and cancers. Ubiquilins (UBQLNs) are versatile proteins that engage with many components of protein quality control (PQC) machinery in cells. Disease-linked mutations of UBQLNs are most commonly associated with amyotrophic lateral sclerosis (ALS), frontotemporal dementia (FTD), and other neurodegenerative disorders. UBQLNs play well-established roles in PQC processes, including facilitating degradation of substrates through the ubiquitin-proteasome system (UPS), autophagy, and endoplasmic-reticulum-associated protein degradation (ERAD) pathways. In addition, UBQLNs engage with chaperones to sequester, degrade, or assist repair of misfolded client proteins. Furthermore, UBQLNs regulate DNA damage repair mechanisms, interact with RNA-binding proteins (RBPs), and engage with cytoskeletal elements to regulate cell differentiation and development. Important to the myriad functions of UBQLNs are its multidomain architecture and ability to self-associate. UBQLNs are linked to numerous types of cellular puncta, including stress-induced biomolecular condensates, autophagosomes, aggresomes, and aggregates. In this review, we focus on deciphering how UBQLNs function on a molecular level. We examine the properties of oligomerization-driven interactions among the structured and intrinsically disordered segments of UBQLNs. These interactions, together with the knowledge from studies of disease-linked mutations, provide significant insights to UBQLN structure, dynamics and function.

Keywords: autophagy; oligomerization; protein aggregation; protein quality control; ubiquilins (UBQLNs); ubiquitin proteasome system.

Publication types

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

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics
  • Amyotrophic Lateral Sclerosis / metabolism
  • Animals
  • Autophagy*
  • Autophagy-Related Proteins* / chemistry
  • Autophagy-Related Proteins* / genetics
  • Autophagy-Related Proteins* / metabolism
  • DNA Repair*
  • Endoplasmic Reticulum-Associated Degradation*
  • Frontotemporal Dementia / genetics
  • Frontotemporal Dementia / metabolism
  • Humans
  • Mutation
  • Nuclear Proteins / chemistry
  • Nuclear Proteins / genetics
  • Nuclear Proteins / metabolism
  • Proteasome Endopeptidase Complex / genetics
  • Proteasome Endopeptidase Complex / metabolism
  • Protein Domains
  • Structure-Activity Relationship
  • Ubiquitin / genetics
  • Ubiquitin / metabolism

Substances

  • Autophagy-Related Proteins
  • Nuclear Proteins
  • Ubiquitin
  • Proteasome Endopeptidase Complex