Cullin mediated protein turnover in skeletal and cardiac muscles The regulated degradation of proteins is an important mechanism for the survival of cells. Accumulation of undegraded proteins in aggrosomes/inclusion bodies, or the premature degradation of (mutant) proteins is often associated with development of diseases, like cardiac and skeletal muscle myopathies. Cardiac and skeletal muscle cells contain up to four proteolytic systems for the degradation of myofbrillar proteins: the caspase and calpain proteases, the ubiquitin-proteasome system (UPS), and the autophagy system. Degradation of most cellular proteins is achieved by way of the UPS and requires tagging of substrate proteins by ubiquitin (poly-ubiquitylation) through an enzymatic cascade. Recognition of substrate and its subsequent ubiquitylation involves the concerted action of E3-ubiquitin ligases and E2-ubiquitin conjugating enzymes. Intriguingly, several components involved in the ubiquitylation of muscle proteins are localized along myofibrils, like the muscle specific E3-ligases of the MuRF protein family. While considerable attention has been focused on these muscle specific UPS components, there is limited information on the role of the more ubiquitously expressed E3-ligases in muscle protein turnover, and whether they may play a more causal role for the development and progression of myopathies. While investigating the obscurin family of myofibrillar proteins, we identified several previously uncharacterized links to cullin-RING proteins, a large family of ubiquitin E3-ligases. Moreover we found that some of these cullin proteins exhibit a myofibrillar localization, comparable to muscle specific E3-ligases. These intriguing results, and the observation that cullin-RING ligases are altered in models for dilated cardiomyopathy (MLP knockout mouse) and skeletal muscle myopathy (obscurin knockout) led us to the hypothesis that cullin-3 and its associated proteins may play a greater role for muscle protein turnover than previously anticipated. The proposed research project investigates the biological role of cullin proteins for muscle specific protein- turnover, and their links to myofibrillar proteins of the obscurin protein family, through a combination of in vivo approaches that analyze cardiac and skeletal muscle physiology and function, with in vitro methods that characterize cullin-3, its binding partners, and their association to obscurin proteins at the molecular level. Preliminary studies indicate that results from this project may have ramifications not only for skeletal muscle myopathies, like the limb-girdle muscular dystrophy (type 2J) through links with obscurin proteins, but also for cardiomyopathies, since cullin proteins, and some of their binding partners are significantly altered in animal models for dilated cardiomyopathy (MLP knockout).
The project 'Cullin mediated protein turnover in skeletal and cardiac muscles' investigates the biological function of cullin proteins, a class of enzymes that is important for protein degradation. Particularly the role of cullin-3, and its binding partners, for the proper development and physiological function for heart and skeletal muscles will be analyzed. Preliminary studies indicate that results from this project may have ramifications not only for skeletal muscle myopathies, like the limb-girdle muscular dystrophy (type 2J) through links with obscurin proteins, but also for cardiomyopathies, since cullin proteins, and some of their binding partners are significantly altered in animal models for dilated cardiomyopathy (MLP knockout).
|Blondelle, Jordan; Shapiro, Paige; Domenighetti, Andrea A et al. (2017) Cullin E3 Ligase Activity Is Required for Myoblast Differentiation. J Mol Biol 429:1045-1066|
|Randazzo, D; Blaauw, B; Paolini, C et al. (2017) Exercise-induced alterations and loss of sarcomeric M-line organization in the diaphragm muscle of obscurin knockout mice. Am J Physiol Cell Physiol 312:C16-C28|
|Bogomolovas, Julius; Fleming, Jennifer R; Anderson, Brian R et al. (2016) Exploration of pathomechanisms triggered by a single-nucleotide polymorphism in titin's I-band: the cardiomyopathy-linked mutation T2580I. Open Biol 6:|
|Lange, Stephan; Gehmlich, Katja; Lun, Alexander S et al. (2016) MLP and CARP are linked to chronic PKC? signalling in dilated cardiomyopathy. Nat Commun 7:12120|
|Mu, Yongxin; Jing, Ran; Peter, Angela K et al. (2015) Cypher and Enigma homolog protein are essential for cardiac development and embryonic survival. J Am Heart Assoc 4:|
|Blondelle, Jordan; Lange, Stephan; Greenberg, Barry H et al. (2015) Cathepsins in heart disease-chewing on the heartache? Am J Physiol Heart Circ Physiol 308:H974-6|
|Banerjee, Indroneal; Carrion, Katrina; Serrano, Ricardo et al. (2015) Cyclic stretch of embryonic cardiomyocytes increases proliferation, growth, and expression while repressing Tgf-? signaling. J Mol Cell Cardiol 79:133-44|
|Lun, Alexander Shiang; Chen, Ju; Lange, Stephan (2014) Probing muscle ankyrin-repeat protein (MARP) structure and function. Anat Rec (Hoboken) 297:1615-29|
|Roth, Gretchen M; Bader, David M; Pfaltzgraff, Elise R (2014) Isolation and physiological analysis of mouse cardiomyocytes. J Vis Exp :e51109|
|Lange, Stephan; Edström, Lars; Udd, Bjarne et al. (2014) Reply: Hereditary myopathy with early respiratory failure is caused by mutations in the titin FN3 119 domain. Brain 137:e279|
Showing the most recent 10 out of 14 publications