CMYA5 is a novel interaction partner of FHL2 in cardiac myocytes

Four‐and‐a‐half LIM domains protein 2 (FHL2) is an anti‐hypertrophic adaptor protein that regulates cardiac myocyte signalling and function. Herein, we identified cardiomyopathy‐associated 5 (CMYA5) as a novel FHL2 interaction partner in cardiac myocytes. In vitro pull‐down assays demonstrated interaction between FHL2 and the N‐ and C‐terminal regions of CMYA5. The interaction was verified in adult cardiac myocytes by proximity ligation assays. Immunofluorescence and confocal microscopy demonstrated co‐localisation in the same subcellular compartment. The binding interface between FHL2 and CMYA5 was mapped by peptide arrays. Exposure of neonatal rat ventricular myocytes to a CMYA5 peptide covering one of the FHL2 interaction sites led to an increase in cell area at baseline, but a blunted response to chronic phenylephrine treatment. In contrast to wild‐type hearts, loss or reduced FHL2 expression in Fhl2‐targeted knockout mouse hearts or in a humanised mouse model of hypertrophic cardiomyopathy led to redistribution of CMYA5 into the perinuclear and intercalated disc region. Taken together, our results indicate a direct interaction of the two adaptor proteins FHL2 and CMYA5 in cardiac myocytes, which might impact subcellular compartmentation of CMYA5. Cardiomyopathy‐associated 5 (CMYA5) is a novel interaction partner of four‐and‐a‐half LIM domains protein 2 (FHL2) in cardiac myocytes. This interaction regulates the subcellular distribution of CMYA5. This was evidenced in hearts isolated from Fhl2 knockout or Mybpc3 knock‐in mice, which exhibit no or reduced FHL2 expression respectively.