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UBA1 promotes cardiac hypertrophy by suppressing autophagy via targeting ATG5 for ubiquitination

Qiu-Yue Lin1, Wei-Jia Yu2, Jia-Xin Li2

  • 1Institute of Cardiovascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, 116000, China. lqy8986@163.com.

Cell Communication and Signaling : CCS
|March 1, 2026
PubMed

Insights

UBA1 (ubiquitin-activating enzyme 1) promotes cardiac hypertrophy by degrading ATG5, inhibiting autophagy. Targeting UBA1 may treat hypertrophic cardiomyopathy and heart failure.

Area of Science:

  • Cardiovascular Biology
  • Molecular Mechanisms of Disease
  • Cellular Signaling

Background:

  • Pathological cardiac hypertrophy is a precursor to heart failure.
  • The role of UBA1 (ubiquitin-activating enzyme 1) in cardiac hypertrophy is not well understood.
  • UBA1 is crucial for ubiquitin-proteasome system signaling.

Purpose of the Study:

  • To investigate the mechanism of UBA1 in cardiac hypertrophy.
  • To determine if UBA1 is a viable therapeutic target for hypertrophic cardiomyopathy.

Main Methods:

  • Cardiac hypertrophy was induced using Ang II stimulation and transverse aortic constriction (TAC) in vitro and in vivo.
  • UBA1 levels were manipulated using rAAV9-UBA1-siRNA (knockdown) and rAAV9-UBA1 (overexpression) in mice.
  • Interactions between UBA1 and ATG5 were analyzed, along with autophagy markers and cardiac function.

Main Results:

  • UBA1 expression was elevated in human and murine hypertrophic hearts.
  • UBA1 knockdown protected against TAC-induced hypertrophy, fibrosis, oxidative stress, and dysfunction.
  • UBA1 directly targeted ATG5 for ubiquitination and degradation, inhibiting autophagy and promoting hypertrophy. ATG5 deletion abolished UBA1 knockdown's protective effects.

Conclusions:

  • UBA1 drives cardiac hypertrophy by suppressing ATG5-mediated autophagy.
  • UBA1 represents a potential therapeutic target for treating hypertrophic cardiomyopathy.
Abstract

Keywords:
ATG5AutophagyCardiac hypertrophyUBA1Ubiquitination

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