SLIMMER (FHL1B/KyoT3) Interacts with the Proapoptotic Protein Siva-1 (CD27BP) and Delays Skeletal Myoblast Apoptosis

Abstract

The fhl1 gene encoding four-and-a-half LIM protein-1 (FHL1) and its spliced isoform, SLIMMER, is mutated in reducing body myopathy, X-linked myopathy with postural muscle atrophy, scapuloperoneal myopathy, and rigid spine syndrome. In this study we have identified a novel function for SLIMMER in delaying skeletal muscle apoptosis via an interaction with the proapoptotic protein Siva-1. Siva-1 was identified as a SLIMMER-specific-interacting protein using yeast two-hybrid screening, direct-binding studies, and glutathione S-transferase pulldown analysis of murine skeletal muscle lysates. In C2C12 skeletal myoblasts, SLIMMER and Siva co-localized in the nucleus; however, both proteins exhibited redistribution to the cytoplasm following the differentiation of mononucleated myoblasts to multinucleated myotubes. In sections of mature skeletal muscle from wild type mice, SLIMMER and Siva-1 colocalized at the Z-line. SLIMMER and Siva-1 were also enriched in Pax-7-positive satellite cells, muscle stem cells that facilitate repair and regeneration. Significantly, SLIMMER delayed Siva-1-dependent apoptosis in C2C12 myoblasts. In skeletal muscle sections from the mdx mouse model of Duchenne muscular dystrophy, SLIMMER and Siva-1 co-localized in the nucleus of apoptotic myofibers. Therefore, SLIMMER may protect skeletal muscle from apoptosis.

p53 target Siva regulates apoptosis in ischemic kidneys

“…In addition to its interaction with TNFR superfamily members, Siva has also been shown to interact with anti-apoptotic Bcl-X L and sensitize MCF7 breast cancer cells to UV-induced apoptosis (48). Similarly, recent reports indicate that Siva can bind to lysophosphatidc acid recptor 2 (25, 40a), the adaptor protein TRAF2 in Jurkat T leukemia cells to modulate NF-B activity (14), pyrin in possibly human neutrophils, monocytes, and synovial cells (3) and with slimmer in skeletal myoblasts to delay apoptosis (8). Of two Siva splice variants (Siva-1 and Siva-2), the predominant form, Siva-1, retains the exon2 and it is believed to be critical for apoptotic activity (49).…”

Pretreatment with insulin-like growth factor I protects skeletal muscle cells against oxidative damage via PI3K/Akt and ERK1/2 MAPK pathways

“…It seems that 2-h exposure caused more apoptosis than 1-h exposure. To validate the method, camptothecin that has been proven to be able to induce muscle cell apoptosis previously, 13 was included in the experiment as a positive control. It was found that exposure to camptothecin for 2 h also caused apoptosis in both cell lines.…”

The Pathogenesis and Therapies of Striated Muscle Laminopathies

“…Beside this location at the nuclear envelope, the various FHL1 isoforms have been reported at different locations within the cell: at the focal adhesions where it regulates cell migration via integrins (Robinson et al, 2003 ); in the sarcomeres where it interacts with MyBP-c as well as with titin and it is involved in sarcomere formation and in the stress-response signaling via activation of the MAPK signaling (McGrath et al, 2006 ; Sheikh et al, 2008 ); and in the nucleus where it interacts with various transcriptional factors (like NFAT proteins or RBP-J) involved in cell proliferation and differentiation but also with the pro-apoptotic protein Siva where it is involved in cell survival (Taniguchi et al, 1998 ; Schulz and Yutzey, 2004 ; Liang et al, 2008 ; Cottle et al, 2009 ).…”