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In Vitro Ubiquitination and Deubiquitination Assays of Nucleosomal Histones
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Deubiquitinase OTUD3 regulates metabolism homeostasis in response to nutritional stresses

Na Zhou1, Hailong Qi2, Junjun Liu3

  • 1Institute of Systems Biomedicine, Department of Pathology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; Department of Clinical Laboratory, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, Shandong 250021, China.

Cell Metabolism
|June 8, 2022
PubMed

Insights

A rare OTUD3 mutation linked to early diabetes impairs its function, leading to obesity and insulin resistance in mice. Targeting PPARδ may offer therapeutic benefits for metabolic disorders.

Area of Science:

  • Biochemistry
  • Genetics
  • Metabolic Research

Background:

  • Ovarian-tumor-domain-containing deubiquitinases (OTUDs) regulate protein degradation and signaling.
  • OTUD3's role in energy metabolism is not fully understood.
  • A novel OTUD3 mutation (c.863G>A) was identified in a family with early-onset diabetes.

Purpose of the Study:

  • To investigate the functional impact of the OTUD3 c.863G>A mutation.
  • To elucidate OTUD3's role in regulating glucose and lipid metabolism.
  • To explore therapeutic strategies targeting OTUD3-mediated pathways.

Main Methods:

  • Characterization of the OTUD3 c.863G>A mutation's effect on protein stability and activity.
  • Analysis of Otud3 knockout (Otud3-/-) mice fed a high-fat diet (HFD).
  • Investigation of OTUD3 acetylation, nuclear translocation, and interaction with PPARδ.

Main Results:

  • The OTUD3 mutation reduced protein stability and catalytic activity.
  • Otud3-/- mice exhibited exacerbated obesity, dyslipidemia, and insulin resistance under HFD.
  • OTUD3 regulates glucose and lipid metabolism genes by stabilizing PPARδ, influenced by glucose and fatty acid levels.
  • PPARδ agonist treatment partially rescued the HFD-induced phenotype in Otud3-/- mice.

Conclusions:

  • OTUD3 is a critical regulator of energy metabolism.
  • The OTUD3 c.863G>A mutation is associated with obesity and increased diabetes risk.
  • Modulating PPARδ activity presents a potential therapeutic avenue for OTUD3-related metabolic dysfunction.
Keywords:
OTUD3PPARδacetylationmetabolic homeostasisnuclear translocation

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