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Journal of Biochemistry Advance Access originally published online on February 22, 2008
Journal of Biochemistry 2008 143(6):765-772; doi:10.1093/jb/mvn027
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© 2008 The Japanese Biochemical Society

Specific Regulation of Cytokine-Dependent p38 MAP Kinase Activation by p62/SQSTM1

Kayoko Kawai1,2, Akiko Saito1, Tatsuhiko Sudo1,* and Hiroyuki Osada1,2

1Antibiotics Laboratory and Bioarchitect Research Group, DRI, RIKEN, 2-1 Hirosawa, Wako, Saitama, 351-0198; and 2Graduate School of Science and Engineering, Saitama University, 255 Shimo-okubo, Saitama, Saitama, 338-8570, Japan

*To whom correspondence should be addressed. Tel: +81 48 467 9542, Fax: +81 48 462 4669, E-mail: sudo{at}riken.jp

Received December 5, 2007; Accepted February 16, 2008


  Abstract

We have previously shown that p62/SQSTM1 binds to p38. In this study, we identified two association domains of p62 to p38 by conducting co-immunoprecipitation experiments. One domain comprises the amino acids 173–182, named N-terminal p38 interaction (NPI) domain, and the other domain comprises the amino acids 335–344, named C-terminal p38 interaction (CPI) domain. An aspartic acid tripeptide located at 335–337 was required for their association. However, the direct interaction was only observed between the recombinant p38 and the peptide of the NPI domain, but not that of the CPI domain in the surface plasmon resonance analyses. These results suggest that the CPI domain may serve to form a certain conformation suitable for the association with p38. Furthermore, we showed that knockdown of p62 expression by siRNA led to impaired p38 phosphorylation only when HeLa cells were stimulated by cytokine. The critical role of p62 in cytokine-dependent p38 signalling pathway was further confirmed by measuring IL-8 mRNA. Cytokine mRNA is often stabilized via p38 pathway. In the absence of p62, IL-8 mRNA induced by IL-1β became more fragile. These data show that p62 specifically regulates cytokine-dependent p38 signalling pathway.

Key Words: cytokine, p38, p62, Paget's disease of bone, safety catch

Abbreviations: IL, interleukin; NF-{kappa}B, nuclear factor {kappa}B; p38, p38 mitogen-activated protein kinase; siRNA, small interfering RNA; SPR, surface plasmon resonance; SQSTM1, sequestosome1; TNF, tumour necrosis factor


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