The 16 kDa subunit of vacuolar H+-ATPase is a novel sarcoglycan-interacting protein.
The sarcoglycan complex in muscle consists of alpha-, beta-, gamma- and delta-sarcoglycan and is part of the larger dystrophin-glycoprotein complex (DGC), which is essential for maintaining muscle membrane integrity. Mutations in any of the four sarcoglycans cause limb-girdle muscular dystrophies (LGMD). In this report, we have identified a novel interaction between delta-sarcoglycan and the 16 kDa subunit c (16K) of vacuolar H(+)-ATPase. Co-expression studies in heterologous cell system revealed that 16K interacts specifically with delta-sarcoglycan and the highly related gamma-sarcoglycan through the transmembrane domains. In cultured C2C12 myotubes, 16K forms a complex with sarcoglycans at the plasma membrane. Loss of sarcoglycans in the sarcoglycan-deficient BIO14.6 hamster destabilizes the DGC and alters the localization of 16K at the sarcolemma. In addition, the steady state level of beta(1)-integrin is increased. Recent studies have shown that 16K also interacts directly with beta(1)-integrin and our data demonstrated that sarcoglycans, 16K and beta(1)-integrin were immunoprecipitated together in C2C12 myotubes. Since sarcoglycans have been proposed to participate in bi-directional signaling with integrins, our findings suggest that 16K might mediate the communication between sarcoglycans and integrins and play an important role in the pathogenesis of muscular dystrophy.
Chen
Jiwei
J
Sigfried and Janet Weis Center for Research, The Geisinger Clinic, Danville, PA 17822, USA.
Skinner
Mhairi A
MA
Shi
Weixing
W
Yu
Qian-Chun
QC
Wildeman
Alan G
AG
Chan
Yiu-mo Michael
YM
D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D002522:Chlorocebus aethiops; D006224:Cricetinae; D019012:Integrin beta1 / Q000378:metabolism; D008297:Male; D051379:Mice; D016253:Microscopy, Immunoelectron; D018485:Muscle Fibers, Skeletal / Q000378:metabolism / Q000648:ultrastructure; D018482:Muscle, Skeletal / Q000378:metabolism; D011485:Protein Binding; D021122:Protein Subunits / Q000378:metabolism; D049031:Sarcoglycans / Q000378:metabolism*; D012508:Sarcolemma / Q000378:metabolism / Q000648:ultrastructure; D015398:Signal Transduction; D025262:Vacuolar Proton-Translocating ATPases / Q000378:metabolism*
D019012:Integrin beta1; D021122:Protein Subunits; D049031:Sarcoglycans; D025262:Vacuolar Proton-Translocating ATPases