E3 ubiquitin ligase RNF5 attenuates pathological cardiac hypertrophy through STING

Area of Science:

• Cardiovascular Biology
• Molecular Cell Biology
• Immunology

Background:

• Ring-finger protein 5 (RNF5) is an E3 ubiquitin ligase implicated in endoplasmic reticulum stress, inflammation, and tumorigenesis.
• The role of RNF5 in cardiac hypertrophy, a significant cardiovascular condition, remains uninvestigated.
• Pathological cardiac hypertrophy involves complex molecular signaling pathways that are not fully understood.

Purpose of the Study:

• To investigate the role of Ring-finger protein 5 (RNF5) in the development of cardiac hypertrophy.
• To elucidate the molecular mechanism by which RNF5 influences cardiac hypertrophy.
• To explore the potential of RNF5 as a therapeutic target for cardiac hypertrophy.

Main Methods:

• Quantitative analysis of RNF5 expression in mouse models of cardiac hypertrophy.
• Loss-of-function and gain-of-function studies utilizing RNF5-deficient and overexpressing models.
• Protein-protein interaction assays to determine the relationship between RNF5 and STING.
• Ubiquitination assays to analyze the mechanism of STING degradation.

Main Results:

• RNF5 expression was significantly upregulated in the hearts of mice with pathological cardiac hypertrophy.
• RNF5 deficiency exacerbated cardiac hypertrophy, whereas RNF5 overexpression attenuated it.
• RNF5 directly interacted with STING (stimulator of interferon genes).
• RNF5 promoted the degradation of STING via K48-linked polyubiquitination, thereby inhibiting cardiac hypertrophy.

Conclusions:

• RNF5 plays a critical protective role in mitigating cardiac hypertrophy.
• The RNF5-STING axis represents a novel signaling pathway regulating cardiac hypertrophy.
• Targeting RNF5 may offer a potential therapeutic strategy for treating cardiac hypertrophy.