| Summary: | Skeletal muscle consists of an extremely regular organization of myofibers that are specialized in contraction. Development and maintenance of skeletal muscle function depends on the precise organization of sarcomeric contractile proteins that consist the myofibrils. Impaired or delayed myofibrillogenesis has been identified as the primary pathological mechanism of many skeletal muscle myopathies. Several members of the Kelch family of proteins have been implicated in skeletal muscle development and diseases, and mutations in these proteins have resulted in perturbations in the ubiquitin proteasome system (UPS), which is the primary means of proteasomal degradation in eukaryotes. In particular, KLHL41 of the BTB-BACK Kelch family is primarily expressed in skeletal muscle and has been identified as a regulator of the skeletal muscle differentiation process that results in the normal development and functioning of mature skeletal muscles. KLHL41 acts as a substrate-specific adaptor for Cullin 3 (Cul3) E3 ubiquitin ligase, implicating the role/s of KLHL41 in proteasomal ubiquitination processes in skeletal muscle. Recent studies have determined that the degradation of nebulin-related anchoring protein (NRAP), which was found to interact with KLHL41, is a critical process in skeletal myofibril maturation that is caused by KLHL41-mediated ubiquitination of the NRAP protein. Through this study, it was further confirmed that KLHL41 changes in localization as maturation occurs, which may provide insight into the mechanism of its functions in myofibril maturation. In addition, the study found that KLHL41 promotes the critical process of nebulin-related anchoring protein (NRAP) degradation. Lastly, mutations in the KLHL41, which are known to cause Nemaline Myopathy (NM) in patients, were modeled in murine C2C12 myoblasts to gain a greater understanding of how KLHL41 mutations may affect protein stability and Cul3 E3 ubiquitin ligase activity. Overall, the findings of this thesis support the critical role of KLHL41 in the formation of mature myofibrils, and provides insight into how deficiency of KLHL41 contributes to a disease state through regulation of the CUL3 protein complex. === 2022-06-30T00:00:00Z
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