Formin follows function: a muscle-specific isoform of FHOD3 is regulated by CK2 phosphorylation and promotes myofibril maintenance

Abstract

Phosphorylation of the muscle-specific formin splice variant FHOD3 by CK2 regulates its stability, myofibril targeting, and myofibril integrity.

Actin in striated muscle: recent insights into assembly and maintenance

“…Interestingly, the subcellular localisation of FHOD3 depends on the maturity/ developmental stage of the myofibrils. In freshly isolated rod-shaped adult cardiomyocytes and in heart tissue sections, FHOD3 is restricted to the Z-disc region, while in neonatal rat cardiomyocytes that adapt to cell culture conditions, both the endogenous as well as transfected, epitopetagged, full-length FHOD3 distribute in a much broader pattern (Iskratsch and Ehler 2011;Iskratsch et al 2010). Incidentally, a similar transition in localisation was also seen in the work on N-WASP (Takano et al 2010).…”

“…FHOD3 clearly plays a role in the maintenance of myofibrils in cultured cardiomyocytes, since its knockdown in culture leads to their fragmentation (Iskratsch et al 2010;Taniguchi et al 2009). In addition, we were able to demonstrate that FHOD3 also enhances the recovery of actin filaments in cardiomyocytes following latrunculin B treatment and that it does this in a much more efficient way than one of the classical formins, mDia1 (Iskratsch et al 2010). Since the expression of FHOD3 is also downregulated in human heart failure, we proposed a crucial general role for this protein in the maintenance of myofibrils in a healthy heart.…”

“…Phosphorylation by CK2, which is a ubiquitously expressed kinase, could be shown in vitro and in vivo and governs the subcellular localisation of muscle FHOD3 as well as the increased half-life of this isoform (Iskratsch et al 2010). FHOD3 clearly plays a role in the maintenance of myofibrils in cultured cardiomyocytes, since its knockdown in culture leads to their fragmentation (Iskratsch et al 2010;Taniguchi et al 2009). In addition, we were able to demonstrate that FHOD3 also enhances the recovery of actin filaments in cardiomyocytes following latrunculin B treatment and that it does this in a much more efficient way than one of the classical formins, mDia1 (Iskratsch et al 2010).…”

“…Formins tend to act as dimers through dimerisation via their FH2 domains and usually elongate filaments by remaining associated with them, allowing rapid addition of actin monomers (Goode and Eck 2007). We managed to clone a novel, striated muscle-specific isoform of the formin FHOD3, which is characterised by the possession of eight additional amino acids that make up a CK2 (casein kinase) phosphorylation site (Iskratsch et al 2010). Phosphorylation by CK2, which is a ubiquitously expressed kinase, could be shown in vitro and in vivo and governs the subcellular localisation of muscle FHOD3 as well as the increased half-life of this isoform (Iskratsch et al 2010).…”

“…We managed to clone a novel, striated muscle-specific isoform of the formin FHOD3, which is characterised by the possession of eight additional amino acids that make up a CK2 (casein kinase) phosphorylation site (Iskratsch et al 2010). Phosphorylation by CK2, which is a ubiquitously expressed kinase, could be shown in vitro and in vivo and governs the subcellular localisation of muscle FHOD3 as well as the increased half-life of this isoform (Iskratsch et al 2010). FHOD3 clearly plays a role in the maintenance of myofibrils in cultured cardiomyocytes, since its knockdown in culture leads to their fragmentation (Iskratsch et al 2010;Taniguchi et al 2009).…”