Sorting nexin 3 induces myocardial injury via promoting retromer-dependent nuclear trafficking of STAT3

Sorting nexins (SNXs), the retromer-associated cargo binding proteins, have emerged as critical regulators of the trafficking of proteins involved in the pathogenesis of diverse diseases. However, studies of SNXs in the development of cardiovascular diseases, especially pathological cardiac hypertrophy, are lacking. Here, we asked whether SNX3, the simplest structured isoform in the SNXs family, may act as a key inducer of myocardial injury. We reported that increased level of SNX3 was observed in failing hearts from human patients and mice. Cardiac-specific Snx3 knockout (Snx3-cKO) in mice significantly protected against isoproterenol (ISO) -induced cardiac injury at 12 weeks. Conversely, cardiac-specific Snx3 transgenic (Snx3-cTg) mice were more susceptible to ISO-induced cardiac injury at 12 weeks, and showed aggravated cardiac injury even heart failure at 24 weeks. Immunoprecipitation-based mass spectrometry (IP-MS), immunofluorescent staining, co-immunoprecipitation and localized surface plasmon resonance (LSPR) were performed to examine the direct interaction of SNX3-retromer with STAT3. STAT3 was discovered as a new interacting partner of SNX3-retromer, and SNX3-retromer served as an essential platform for assembling gp130/JAK2/STAT3 complexes and subsequent phosphorylation of STAT3 by direct combination at early endosomes. SNX3-retromer and STAT3 complexes were transiently imported into the nucleus after hypertrophic stimuli. Moreover, SNX3-retromer promoted importin α3-mediated STAT3 nuclear trafficking and ultimately leading to cardiac injury. Also, pharmacological inhibition of STAT3 reversed SNX3 overexpression-induced myocardial injury in vivo and in vitro. Taken together, our study reveals that SNX3 plays a key role in cardiac function and implicates SNX3 as a potential therapeutic target for cardiac hypertrophy and heart failure.