Why the study?
Loss of the cytoskeletal protein betaIV-spectrin depends on CaMKII and promotes cardiac fibroblast activation, but the specific mechanism remained unknown.
CaMKII-dependent phosphorylation of βIV-spectrin drives its degradation and promotes profibrotic signaling in cardiac fibroblasts, highlighting a potential mechanism and therapeutic target for cardiac fibrosis.
Links CaMKII to βIV-spectrin loss in fibroblast activation; leaves open whether targeting this pathway reduces cardiac fibrosis.
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 β IV -spectrin as an important step in CF activation and cardiac fibrosis. Furthermore, loss of β IV -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 β IV -spectrin and CF activity. Computational screening and MS revealed a critical serine residue (S2250 in mouse and S2254 in human) in β IV -spectrin phosphorylated by CaMKII. Disruption of β IV -spectrin/CaMKII interaction or alanine substitution of β IV -spectrin Ser2250 (β IV -S2254A) prevented CaMKII-induced degradation, whereas a phosphomimetic construct (β IV -spectrin with glutamic acid substitution at serine 2254 [β IV -S2254E]) showed accelerated degradation in the absence of CaMKII. To assess the physiological significance of this phosphorylation event, we expressed exogenous β IV -S2254A and β IV -S2254E constructs in β IV -spectrin-deficient CFs, which have increased proliferation and fibrotic gene expression compared with WT CFs. β IV -S2254A but not β IV -S2254E normalized CF proliferation, gene expression, and contractility. Pathophysiological targeting of β IV -spectrin phosphorylation and subsequent degradation was identified in CFs activated with the profibrotic ligand angiotensin II, resulting in increased proliferation and signal transducer and activation of transcription 3 nuclear accumulation. While therapeutic delivery of exogenous WT β IV -spectrin partially reversed these trends, β IV -S2254A completely negated increased CF proliferation and signal transducer and activation of transcription 3 translocation. Moreover, we observed β IV -spectrin phosphorylation and associated loss in total protein within human heart tissue following heart failure. Together, these data illustrate a considerable role for the β IV -spectrin/CaMKII interaction in activating profibrotic signaling.
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Nassal et al. (2021) studied this question.
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