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. 2004 Jul 27;101(30):10990-4.
doi: 10.1073/pnas.0403546101. Epub 2004 Jul 15.

Integration of Caenorhabditis elegans MAPK pathways mediating immunity and stress resistance by MEK-1 MAPK kinase and VHP-1 MAPK phosphatase

Dennis H Kim  1 , Nicole T Liberati, Tomoaki Mizuno, Hideki Inoue, Naoki Hisamoto, Kunihiro Matsumoto, Frederick M Ausubel
Affiliations

Integration of Caenorhabditis elegans MAPK pathways mediating immunity and stress resistance by MEK-1 MAPK kinase and VHP-1 MAPK phosphatase

Dennis H Kim et al. Proc Natl Acad Sci U S A. .

Abstract

The p38 and JNK classes of mitogen-activated protein kinases (MAPKs) have evolutionarily conserved roles in the control of cellular responses to microbial and abiotic stresses. The mechanisms by which crosstalk between distinct p38 and c-Jun N-terminal kinase (JNK) MAPK pathways occurs with resultant integration of signaling information have been difficult to establish, particularly in the context of whole organism physiology. In Caenorhabditis elegans a PMK-1 p38 MAPK pathway is required for resistance to bacterial infection, and a KGB-1 JNK-like MAPK pathway has recently been shown to mediate resistance to heavy metal stress. Here, we show that two components of the KGB-1 pathway, MEK-1 MAPK kinase (MAPKK), a homolog of mammalian MKK7, and VHP-1 MAPK phosphatase (MKP), a homolog of mammalian MKP7, also regulate pathogen resistance through the modulation of PMK-1 activity. The regulation of p38 and JNK-like MAPK pathways mediating immunity and heavy metal stress by common MAPKK and MKP signaling components suggests pivotal roles for MEK-1 and VHP-1 in the integration of diverse stress signals contributing to pathogen resistance in C. elegans. In addition, these data point to mechanisms in multicellular organisms by which signals transduced by distinct MAPK pathways may be subject to physiological integration at the level of regulation of MAPK activity by MAPKKs and MKPs.

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Figures

Fig. 1.
Fig. 1.
Requirement for MEK-1 and SEK-1 in the activation of PMK-1 in C. elegans immunity. (A) Pathogen susceptibility of C. elegans mek-1(ks54), sek-1(km4), mek-1(ks54);sek-1(km4), pmk-1(km25), and kgb-1(km21) mutants. At least 40 L4-stage worms were allowed to feed on lawns of P. aeruginosa strain PA14 and were scored as dead when they no longer responded to touch as described in ref. . Representative plots of multiple experiments are shown. All mutant alleles are deletions that are predicted to be null alleles. (B) Immunoblot analysis of PMK-1 activation in young adult whole worm lysates of mek-1(ks54), sek-1(km4), and WT worms by using Abs specific for the doubly phosphorylated activated form of PMK-1 (anti-phospho-p38). Anti-β-tubulin was used as a loading control.
Fig. 2.
Fig. 2.
Effect of RNAi of pmk-1 on the pathogen susceptibility of WT (A), sek-1(km4) (B), and mek-1(ks54) (C) worms. Synchronized populations of L1 larvae for each strain were propagated on E. coli HT115 carrying either vector control (L4440) or pDK177 (pmk-1) as described previously and transferred to lawns of P. aeruginosa strain PA14 at the L4 larval stage. At least 40 worms were scored for each assay and scored as dead when they no longer responded to touch. Representative plots of multiple experiments are shown.
Fig. 3.
Fig. 3.
Modulation of PMK-1 activation by MEK-1 and SEK-1 MAPKKs and VHP-1 MKP: correlation of pathogen susceptibility with levels of PMK-1 activation. Immunoblot analysis of lysates derived from WT and sek-1(km4) and mek-1(ks54) mutants subjected to RNAi by feeding with bacterial strains expressing double-stranded RNA corresponding to the sequence of control (L4440 vector only), pmk-1 (pDK177), or vhp-1 (Ahringer 44D3) genes. Activated levels of PMK-1 were detected by using an Ab (anti-phospho-p38) specific for the doubly phosphorylated form of PMK-1.
Fig. 4.
Fig. 4.
Effect of RNAi of vhp-1 on the Esp phenotype of WT (A) and sek-1(km4) (B) and mek-1(ks54) (C) mutants. Synchronized populations of L1 larvae for each strain were propagated on E. coli HT115 carrying either vector control (L4440) or Ahringer clone 44D3 (vhp-1) as described previously and transferred to lawns of P. aeruginosa strain PA14 at the L4 larval stage. At least 40 worms were scored for each assay and scored as dead when they no longer responded to touch. Representative plots of multiple experiments are shown.
Fig. 5.
Fig. 5.
Integration of distinct PMK-1 p38 MAPK innate immunity and KGB-1 JNK-like MAPK stress response pathways by common MEK-1 MAPKK and VHP-1 MAPK phosphatase signaling components.
See this image and copyright information in PMC

Comment in

  • MAPping innate immunity.
    Young JA, Dillin A. Young JA, et al. Proc Natl Acad Sci U S A. 2004 Aug 31;101(35):12781-2. doi: 10.1073/pnas.0404890101. Epub 2004 Aug 24. Proc Natl Acad Sci U S A. 2004. PMID: 15328410 Free PMC article. No abstract available.

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