TBCE and regulation of microtubule dynamics: Insights from autosomal recessive Kenny-Caffey syndrome.

摘要

Tubulin-binding cofactor E (TBCE) is a chaperone defined initially in the de novo formation of alphabeta-tubulin heterodimers, which in turn are building blocks of microtubules (MTs). Mutations in TBCE cause Autosomal Recessive Kenny-Caffey Syndrome (AR-KCS), a human syndrome characterized by hypoparathyroidism, mental retardation, facial dysmorphia, and growth failure, and a murine model for peripheral motor neuropathy. Analysis of cells from AR-KCS patients revealed markedly diminished levels of TBCE secondary to posttranslational destabilization. Despite such TBCE deficiency, tubulin abundance was maintained, deemphasizing the exclusivity of TBCE chaperone function in vivo. Instead, AR-KCS fibroblasts and lymphoblasts exhibit highly disorganized MT filaments, resulting in aneuploidy and mislocalization of the Golgi apparatus. Furthermore, MT regrowth is compromised in AR-KCS cells and in cells experimentally depleted of TBCE. Together, these findings evidence a novel and critical role for TBCE in the regulation of MT dynamics.; While the majority of TBCE localizes to the cell body, a significant minority tracks along the leading edges of the cell. TBCE also localizes to the kinetochores during mitosis. From data regarding its subcellular localization, function, and structural features, we hypothesized that TBCE likely interacts with members of the plus-end tracking proteins (+TIPs) to affect cellular activities. Indeed, TBCE was found to associate with various +TIP proteins in vitro and in vivo. In addition, TBCE expression impacts specific +TIP specified G-protein signaling pathways. These data demonstrate TBCE as a key regulator of MT filamentous dynamics via novel protein partners and signaling cascades. The discovery of these biologic activities connects, for the first time, the genesis of mature tubulin substrates to their ultimate implementation in microtubules and the critical cellular processes that they subserve.