SPOP Is a Key Trigger of Pathological Cardiac Hypertrophy and Heart Failure

BACKGROUND: Disturbance in protein synthesis and degradation plays a crucial role in various biological and pathological processes. E3 ubiquitin ligase substrate–binding adaptor SPOP (speckle-type POZ [poxvirus and zinc finger] protein) is substantially involved in cancer progression. The study aims to investigate the biological function of SPOP in cardiac hypertrophy and heart failure. METHODS: We generated cardiac-specific transgenic and knockout mice to evaluate the functional role of SPOP in transverse aortic constriction–induced cardiac hypertrophy and heart failure. RNA-sequencing, proteomics, and protein mass spectrometry analysis, and multiple molecular biological methodologies were employed to investigate its function and mechanisms in cardiac hypertrophic mice. RESULTS: SPOP was significantly upregulated in human heart failure, hypertrophic mouse hearts, and Ang II (angiotensin II)–treated neonatal mouse ventricular cardiomyocytes. SPOP induced the expression of hypertrophic markers ANP (atrial natriuretic peptide), BNP (B-type natriuretic peptide), and β-MHC (β-myosin heavy chain), increased cardiomyocyte size, whereas SPOP deficiency exhibited the opposite effects in hypertrophic neonatal mouse ventricular cardiomyocytes. Furthermore, cardiac-specific overexpression of SPOP led to cardiac hypertrophy and heart failure in mice. In contrast, cardiac-specific knockout of SPOP markedly attenuated transverse aortic constriction–induced cardiac hypertrophy and improved heart failure. In parallel, SPOP presented prohypertrophic effects, and SPOP loss-of-function substantially rescued Ang II–induced hypertrophic phenotype in neonatal mouse ventricular cardiomyocytes. Mechanistically, SPOP is transcriptionally activated by p300 under cardiac hypertrophy, subsequently interacting with and promoting ubiquitination-mediated degradation of TFEB (transcription factor EB) independently of its phosphorylation status, a key regulator for transcription of lysosomal biogenesis and autophagy-related genes, leading to blockage of autophagy and mitophagy, which eventually causes cardiac hypertrophy and heart failure. Overexpression of TFEB rescued SPOP-induced these alterations. Noticeably, a specific inhibitor of SPOP was able to prevent the development of cardiac hypertrophy and heart failure. CONCLUSIONS: SPOP is a detrimental factor in pathological cardiac hypertrophy via promoting ubiquitination-induced degradation of TFEB, a critical regulator of the autophagy-lysosomal pathway. Targeting SPOP represents a promising therapeutic strategy for hypertrophy-related heart failure.