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.