Emerging concepts of myosin 18A isoform mechanobiology in organismal and immune system physiology, development, and function

Alternative and combinatorial splicing of myosin 18A (MYO18A) gene transcripts results in expression of MYO18A protein isoforms and isoform variants with different membrane and subcellular localizations, and functional properties. MYO18A proteins are members of the myosin superfamily consisting of a myosin‐like motor domain, an IQ motif, and a coiled‐coil domain. MYO18A isoforms, however, lack the ability to hydrolyze ATP and do not perform ATP‐dependent motor activity. MYO18A isoforms are distinguished by different amino‐ and carboxy‐terminal extensions and domains. The domain organization and functions of MYO18Aα, MYO18Aβ, and MYO18Aγ have been studied experimentally. MYO18Aα and MYO18Aβ have a common carboxy‐terminal extension but differ by the presence or absence of an amino‐terminal KE repeat and PDZ domain, respectively. The amino‐ and carboxy‐terminal extensions of MYO18Aγ contain unique proline and serine‐rich domains. Computationally predicted MYO18Aε and MYO18Aδ isoforms contain the carboxy‐terminal serine‐rich extension but differ by the presence or absence of the amino‐terminal KE/PDZ extension. Additional isoform variants within each category arise by alternative utilization or inclusion/exclusion of small exons. MYO18Aα variants are expressed in somatic cells and mature immune cells, whereas MYO18Aβ variants occur mainly in myeloid and natural killer cells. MYO18Aγ expression is selective to cardiac and skeletal muscle. In the present review perspective, we discuss current and emerging concepts of the functional specialization of MYO18A proteins in membrane and cytoskeletal dynamics, cellular communication and signaling, endocytic and exocytic organelle movement, viral infection, and as the SP‐R210 receptor for surfactant protein A. This study depicts versatile functions of MYO18A isoforms in transcellular and cytoskeletal signaling processes that modulate epithelial barrier integrity, cellular migration and adhesion, viral infection, endosomal trafficking, macrophage functions, structural development of heart and muscle, and integrity of the alveolar capillary barrier. SP‐A and C1q are alveolar and circulating ligands of cell‐surface isoform variants of MYO18Aα and β on innate immune cells.