ABSTRACT
Abstract Bi-allelic mutations in LRBA (from Lipopolysaccharide-responsive and beige-like anchor protein) result in a primary immunodeficiency with clinical features ranging from hypogammaglobulinemia and lymphoproliferative syndrome to inflammatory bowel disease and heterogeneous autoimmune manifestations. LRBA deficiency has been shown to affect vesicular trafficking, autophagy and apoptosis, which may lead to alterations of several molecules and processes that play key roles for immunity. In this review, we will discuss the relationship of LRBA with the endovesicular system in the context of receptor trafficking, autophagy and apoptosis. Since these mechanisms of homeostasis are inherent to all living cells and not only limited to the immune system and also, because they are involved in physiological as well as pathological processes such as embryogenesis or tumoral transformation, we envisage advancing in the identification of potential pharmacological agents to manipulate these processes.
Resumen Las mutaciones bi-alélicas en LRBA (del inglés, Lipopolysaccharide-responsive and beige-like anchor protein) conllevan a una inmunodeficiencia primaria con características clínicas que abarcan desde hipogamaglubulinemia y síndrome linfoproliferativo hasta una enfermedad inflamatoria intestinal y manifestaciones autoinmunes heterogéneas. Se ha demostrado que la deficiencia de LRBA afecta el tráfico vesicular, la autofagia y la apoptosis pudiendo generar alteraciones en la regulación de varios procesos importantes para la inmunidad. En esta revisión discutiremos la relación de LRBA con el sistema endovesicular en el contexto del tráfico de receptores, la autofagia y la apoptosis. Estos mecanismos de homeostasis son inherentes a todas las células y no están limitados a las células del sistema inmune, están involucrados en procesos fisiológicos y patológicos, como la embriogénesis o la transformación tumoral. El entendimiento de la función de LRBA permitirá avanzar en la identificación de los posibles blancos farmacológicos para manipular estos procesos.
ABSTRACT
Membrane repair is a conserved cellular process, where intracellular vesicles translocate to sites of plasma membrane injury to actively reseal membrane disruptions. Such membrane disruptions commonly occur in the course of normal physiology, particularly in skeletal muscles due to repeated contraction producing small tears in the sarcolemmal membrane. Here, we investigated whether prolonged exercise could produce adaptive changes in expression levels of proteins associated with the membrane repair process, including mitsugumin 53/tripartite motif-containing protein 72 (MG53/TRIM72), dysferlin and caveolin-3 (cav3). Mice were exercised using a treadmill running protocol and protein levels were measured by immunoblotting. The specificity of the antibodies used was established by immunoblot testing of various tissue lysates from both mice and rats. We found that MG53/TRIM72 immunostaining on isolated mouse skeletal muscle fibers showed protein localization at sites of membrane disruption created by the isolation of these muscle fibers. However, no significant changes in the expression levels of the tested membrane repair proteins were observed following prolonged treadmill running for eight weeks (30 to 80 min/day). These findings suggest that any compensation occurring in the membrane repair process in skeletal muscle following prolonged exercise does not affect the expression levels of these three key membrane repair proteins.