Abstract
Muscle development requires the coordinated activities of specific protein folding and degradation factors. UFD-2, a U-box ubiquitin ligase, has been reported to play a central role in this orchestra regulating the myosin chaperone UNC-45. Here, we apply an integrative in vitro and in vivo approach to delineate the substrate-targeting mechanism of UFD-2 and elucidate its distinct mechanistic features as an E3/E4 enzyme. Using Caenorhabditis elegans as model system, we demonstrate that UFD-2 is not regulating the protein levels of UNC-45 in muscle cells, but rather shows the characteristic properties of a bona fide E3 ligase involved in protein quality control. Our data demonstrate that UFD-2 preferentially targets unfolded protein segments. Moreover, the UNC-45 chaperone can serve as an adaptor protein of UFD-2 to poly-ubiquitinate unfolded myosin, pointing to a possible role of the UFD-2/UNC-45 pair in maintaining proteostasis in muscle cells.
Highlights
Muscle development requires the coordinated activities of specific protein folding and degradation factors
Using Caenorhabditis elegans as model system, we demonstrate that ubiquitin fusion degradation (UFD)-2 is not regulating the protein levels of UNC-45 in muscle cells, but rather shows the characteristic properties of a bona fide E3 ligase involved in protein quality control
The so far bestcharacterized E4 reaction is the polyubiquitination of UNC-45, mediated by the concerted activities of UFD-2 and CHN-1
Summary
Muscle development requires the coordinated activities of specific protein folding and degradation factors. While CHIP proteins such as CHN-1 function as general qualitycontrol factors marking misfolded, chaperone-bound proteins for proteasomal degradation[29], UFD-2 appears to be a more specific ubiquitination enzyme in higher eukaryotes important for UNC45 regulation and muscle function. Consistent with such a specific role, the mammalian Ufd2a exhibits a remarkably distinctive expression pattern, showing the highest protein levels in skeletal muscle tissue[30]. Ufd2a knockout studies in mice demonstrated that the protein is essential for myocardial development[31]
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