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Molecular and Cellular Biology, December 2003, p. 9127-9135, Vol. 23, No. 24
0270-7306/03/$08.00+0     DOI: 10.1128/MCB.23.24.9127-9135.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.

Calpain 3 Is Activated through Autolysis within the Active Site and Lyses Sarcomeric and Sarcolemmal Components

Mathieu Taveau, Nathalie Bourg, Guillaume Sillon, Carinne Roudaut, Marc Bartoli, and Isabelle Richard*

Généthon, CNRS UMR-8115, 91000 Evry, France

Received 25 June 2003/ Returned for modification 6 August 2003/ Accepted 16 September 2003

Calpain 3 (Capn3) is known as the skeletal muscle-specific member of the calpains, a family of intracellular nonlysosomal cysteine proteases. This enigmatic protease has many unique features among the calpain family and, importantly, mutations in Capn3 have been shown to be responsible for limb girdle muscular dystrophy type 2A. Here we demonstrate that the Capn3 activation mechanism is similar to the universal activation of caspases and corresponds to an autolysis within the active site of the protease. We undertook a search for substrates in immature muscle cells, as several lines of evidence suggest that Capn3 is mostly in an inactive state in muscle and needs a signal to be activated. In this model, Capn3 proteolytic activity leads to disruption of the actin cytoskeleton and disorganization of focal adhesions through cleavage of several endogenous proteins. In addition, we show that titin, a previously identified Capn3 partner, and filamin C are further substrates of Capn3. Finally, we report that Capn3 colocalizes in vivo with its substrates at various sites along cytoskeletal structures. We propose that Capn3-mediated cleavage produces an adaptive response of muscle cells to external and/or internal stimuli, establishing Capn3 as a muscle cytoskeleton regulator.

* Corresponding author. Mailing address: Généthon, CNRS UMR-8115, 1 rue de l'Internationale, 91000 Evry, France. Phone: 33-1 69 47 29 38. Fax: 33-1 60 77 86 98. E-mail: richard{at}genethon.fr.

Molecular and Cellular Biology, December 2003, p. 9127-9135, Vol. 23, No. 24
0022-538X/03/$08.00+0     DOI: 10.1128/MCB.23.24.9127-9135.2003
Copyright © 2003, American Society for Microbiology. All Rights Reserved.



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