| First Author | Nassal DM | Year | 2021 |
| Journal | J Biol Chem | Volume | 297 |
| Issue | 1 | Pages | 100893 |
| PubMed ID | 34153319 | Mgi Jnum | J:307296 |
| Mgi Id | MGI:6720174 | Doi | 10.1016/j.jbc.2021.100893 |
| Citation | Nassal DM, et al. (2021) Ca(2+)/calmodulin kinase II-dependent regulation of betaIV-spectrin modulates cardiac fibroblast gene expression, proliferation, and contractility. J Biol Chem :100893 |
| abstractText | Fibrosis is a pronounced feature of heart disease and the result of dysregulated activation of resident cardiac fibroblasts (CFs). Recent work identified stress-induced degradation of the cytoskeletal protein betaIV-spectrin as an important step in CF activation and cardiac fibrosis. Further, loss of betaIV-spectrin was found to depend on Ca(2+)/calmodulin-dependent kinase II (CaMKII). Therefore, we sought to determine the mechanism for CaMKII-dependent regulation of betaIV-spectrin and CF activity. Computational screening and mass spectrometry revealed a critical serine residue (S2250 in mouse, S2254 in human) in betaIV-spectrin phosphorylated by CaMKII. Disruption of betaIV-spectrin/CaMKII interaction or alanine substitution of betaIV-spectrin Ser2250 (betaIV-S2250A) prevented CaMKII-induced degradation, while a phospho-mimetic construct (betaIV-S2254E) showed accelerated degradation in the absence of CaMKII. To assess the physiological significance of this phosphorylation event, we expressed exogenous betaIV-S2254A and betaIV-S2254E constructs in betaIV-spectrin-deficient CFs, which have increased proliferation and fibrotic gene expression compared to wild-type (WT) CFs. betaIV-S2254A but not betaIV-S2254E normalized CF proliferation, gene expression, and contractility. Pathophysiologic targeting of betaIV-spectrin phosphorylation and subsequent degradation was identified in CFs activated with the profibrotic ligand angiotensin II (AngII), resulting in increased proliferation and STAT3 nuclear accumulation. While therapeutic delivery of exogenous WT betaIV-spectrin partially reversed these trends, betaIV-S2254A completely negated increased CF proliferation and STAT3 translocation. Moreover, we observed betaIV-spectrin phosphorylation and associated loss in total protein within human heart tissue following heart failure (HF). Together, these data illustrate a considerable role for the betaIV-spectrin/CaMKII interaction in activating profibrotic signaling. |
