A new pathway encompassing calpain 3 and its newly identified substrate cardiac ankyrin repeat protein is involved in the regulation of the nuclear factor-κB pathway in skeletal muscle

Lydie Laure, Nathalie Danièle, Laurence Suel, Sylvie Marchand, Sophie Aubert, Nathalie Bourg, Carinne Roudaut, Stephanie Duguez, Marc Bartoli, Isabelle Richard

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Abstract

A multiprotein complex encompassing a transcription regulator, cardiac ankyrin repeat protein (CARP), and the calpain 3 protease was identified in the N2A elastic region of the giant sarcomeric protein titin. The present study aimed to investigate the function(s) of this complex in the skeletal muscle. We demonstrate that CARP subcellular localization is controlled by the activity of calpain 3: the higher the calpain 3, the more important the sarcomeric retention of CARP. This regulation would occur through cleavage of the N-terminal end of CARP by the protease. We show that, upon CARP over-expression, the transcription factor nuclear factor NF-κB p65 DNA-binding activity decreases. Taken as a whole, CARP and its regulator calpain 3 appear to occupy a central position in the important cell fate-governing NF-κB pathway. Interestingly, the expression of the atrophying protein MURF1, one of NF-κB main targets, remains unchanged in presence of CARP, suggesting that the pathway encompassing calpain 3/CARP/NF-κB does not play a role in muscle atrophy. With NF-κB also having anti-apoptotic effects, the inability of calpain 3 to lower CARP-driven inhibition of NF-κB could reduce muscle cell survival, hence partly accounting for the dystrophic pattern observed in limb girdle muscular dystrophy 2A, a pathology resulting from the protease deficiency.
Original languageEnglish
Pages (from-to)4322-4337
JournalThe FEBS journal
Volume277
Issue number20
Early online date28 Sep 2010
DOIs
Publication statusPublished - 23 Oct 2010

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Keywords

  • calpain 3
  • cardiac ankyrin repeat protein
  • limb girdle muscular dystrophy 2A
  • NF-κB
  • skeletal muscle
  • titin

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