Aciculin interacts with filamin C and Xin and is essential for myofibril assembly, remodeling and maintenance

Abstract

Filamin C (FLNc) and Xin actin-binding repeat-containing proteins (XIRPs) are multi-adapter proteins mainly expressed in cardiac and skeletal muscles that play important roles in the assembly and repair of myofibrils and their attachment to the membrane. We identified the dystrophin-binding protein aciculin (PGM5), as a novel interaction partner of FLNc and Xin. All three proteins colocalize at intercalated discs of cardiac muscle and myotendinous junctions of skeletal muscle, while FLNc and aciculin also colocalize in mature Z-discs. Bimolecular fluorescence complementation experiments in developing cultured mammalian skeletal muscle cells demonstrate that Xin and aciculin also interact in FLNc-containing immature myofibrils and areas of myofibrillar remodeling and repair induced by electrical pulse stimulation (EPS). FRAP experiments show that aciculin is a highly dynamic and mobile protein. Aciculin knockdown in myotubes leads to failure in myofibril assembly, alignment and membrane attachment, and massive reduction in myofibril number. A highly similar phenotype was found upon depletion of aciculin in zebrafish embryos. Our results point to a thus far unappreciated but essential function of aciculin in myofibril formation, maintenance and remodeling.

Biology, Mechanism, and Structure of Enzymes in the α- d -Phosphohexomutase Superfamily

“…Enzyme representatives from plants remain woefully understudied, despite their critical functional roles. At the cellular level, very little is known about potential protein-protein interactions involving these enzymes, despite their established importance in some systems (Arimura et al, 2009; Belkin & Burridge, 1994, 1995; Gundlach et al, 2015; Molt et al, 2014) and likelihood in others. A role for post-translation modification in the regulation of enzyme activity, localization, or protein-protein interactions is also a potential new horizon (Dey, Bounelis, Fritz, Bedwell, & Marchase, 1994; Fu et al, 1995; Gururaj, Barnes, Vadlamudi, & Kumar, 2004).…”

“…Its expression is enriched in cardiac, smooth, and skeletal muscle, where it is developmentally regulated. Recently, a detailed study (Molt et al, 2014), established a role for PGM5 (also known as aciculin) in myofibril assembly, remodeling and maintenance, and described its interactions with filamin C (FLNc) and the actin-binding repeat-containing proteins XinA and XinB. PGM5 has also been identified as a binding partner for dystrophin, the protein involved in inherited muscle dystrophy, in skeletal muscle (Belkin & Burridge, 1995).…”

Exome sequencing identifies FLNC and ADD3 variants in a family with cardiomyopathy

“…Filamin C is a dimeric actin-cross-linking protein highly expressed in both skeletal and cardiac muscle, localized to the sarcolemma, Z-disk, and myotendinous junctions, and is associated with structural stability, mechanosensation, and intracellular signaling [21][22][23] . Recently, filamin C was also shown to mediate fast repair of myofibrillar microdamage in cardiomyocytes, in addition to Z-disk assembly [24] .…”

The novel cardiac z-disc protein CEFIP regulates cardiomyocyte hypertrophy by modulating calcineurin signaling

“…5E). Therefore, CEFIP seems to belong to the group of highly dynamic z-disc proteins involved in mechanosensing, signaling, and myofibrillar remodeling (3,16).…”

“…Images were taken before and immediately after bleaching, and fluorescence recovery was monitored for 230 s with an interval time of 0.1-1 s until the signal was fully recovered. Raw data were transformed into normalized FRAP curves as described previously (3,16).…”