Cardiomyocyte OTUD7b drives diabetic cardiomyopathy via deubiquitinating and stabilizing TAK1

Area of Science:

• Cardiovascular Biology
• Molecular Mechanisms of Disease
• Biochemistry

Background:

• Deubiquitinating enzymes (DUBs) play a role in diabetic cardiomyopathy (DCM).
• The specific function of OTU domain-containing protein 7B (OTUD7b) in DCM is currently unknown.
• OTUD7b is a recently identified DUB implicated in cellular processes.

Purpose of the Study:

• To investigate the role of OTUD7b in diabetic cardiomyopathy.
• To elucidate the molecular mechanisms by which OTUD7b affects cardiac function in diabetes.
• To identify potential therapeutic targets for DCM.

Main Methods:

• Analysis of OTUD7b expression in diabetic mouse hearts.
• Cardiomyocyte-specific gene deletion studies in diabetic mice.
• Ubiquitinome and interactome analyses to identify protein substrates.
• Biochemical assays to confirm deubiquitination activity and protein stabilization.
• Assessment of cardiac function, hypertrophy, fibrosis, apoptosis, and inflammatory markers.

Main Results:

• OTUD7b expression is significantly elevated in cardiomyocytes of diabetic mice.
• Cardiomyocyte-specific deletion of OTUD7b ameliorates cardiac dysfunction, hypertrophy, and fibrosis in diabetic mice.
• OTUD7b directly deubiquitinates transforming growth factor β-activated kinase 1 (TAK1) at K346, enhancing its stability.
• This leads to hyperactivation of the TAK1-MAPK axis, promoting apoptosis and inflammation.
• Restoration of a deubiquitination-resistant TAK1 mutant abolished the protective effects of OTUD7b deficiency.

Conclusions:

• OTUD7b drives diabetic heart injury through the deubiquitination and stabilization of TAK1 in cardiomyocytes.
• The novel OTUD7b-TAK1 axis is a key mediator of diabetic cardiomyopathy.
• OTUD7b represents a promising therapeutic target for DCM.