tailieunhanh - Báo cáo khoa học: A new pathway encompassing calpain 3 and its newly identified substrate cardiac ankyrin repeat protein is involved in the regulation of the nuclear factor-jB pathway in skeletal muscle

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. | ễFEBS Journal A new pathway encompassing calpain 3 and its newly identified substrate cardiac ankyrin repeat protein is involved in the regulation of the nuclear factor-KB pathway in skeletal muscle Lydie Laure Nathalie Daniele Laurence Suel Sylvie Marchand Sophie Aubert Nathalie Bourg Carinne Roudaut Stephanie Duguez Marc Bartoli and Isabelle Richard Genethon CNRS UMR8587 LAMBE Evry France Keywords calpain 3 cardiac ankyrin repeat protein limb girdle muscular dystrophy 2A NF-kB skeletalmuscle titin Correspondence I. Richard Genethon CNRS UMR8587 Lambe 1 bis rue de l lnternationale 91000 Evry France Fax 33 0 1 60 77 86 98 Tel 33 0 1 69 47 29 38 E-mail richard@ These authors contributed equally to this work Received 1 June 2010 revised 11 August 2010 accepted 18 August 2010 doi 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-kB 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-kB pathway. Interestingly the expression of the atrophying protein MURF1 one of NF-kB main targets remains unchanged in presence of CARP suggesting that the pathway encompassing cal-pain3 CARP NF-KB does not play a role in muscle atrophy. With NF-kB also having anti-apoptotic effects the inability of calpain 3 to lower CARP-driven inhibition of NF-kB could