Abstract
The p38 mitogen activated protein kinase (MAPK) signaling pathway has been suggested to play a significant role in the gastric mucosal inflammatory response to chronic Helicobacter pylori (H. pylori) infection. Nuclear translocation is thought to be important for p38 function, but no nuclear translocation signals have been found in the protein and no nuclear carrier proteins have been identified for p38. We have investigated the role of small ubiquitin-related modifier (SUMO) in the nuclear transfer of p38 in response to H. pylori infection. Exposure of human AGS cells to H. pylori induced the activation of p38 and the expression of SUMOs, especially SUMO-2. SUMO knockdown counteracted the effect of H. pylori infection by decreasing the resulting p38 mediated cellular apoptosis through a reduction in the nuclear fraction of phosphorylated p38. We identified a non-covalent interaction between SUMOs and p38 via SUMO interaction motifs (SIMs), and showed that SUMO-dependent nuclear transfer of p38 was decreased upon mutation of its SIMs. This study has identified a new pathway of p38 nuclear translocation, in response to H. pylori infection. We conclude that in the presence of H. pylori SUMO-2 has a major role in regulating nuclear levels of p38, through non-covalent SUMO-p38 interactions, independent of the p38 phosphorylation state.
Highlights
Environmental insults such as oxidative stress and hypoxia can induce the activation of the p38 mitogen activated protein kinase (MAPK) signaling pathway, causing a variety of cellular responses such as apoptosis [1,2]. p38 MAPK is activated following phosphorylation at Thr180/Tyr182 within the activation loop (p-p38), primarily by upstream MKK3 and MKK6 [3]. p38 MAPK has been shown to be distributed throughout the cytosol and nucleus [4]
Previous studies have shown that small ubiquitin-related modifier (SUMO) are increased in response to various stresses [16,26,27] and that p38 mRNA and protein are increased in response to H. pylori infection or in response to the H. pylori cytotoxins VacA and CagA [13,14,28], our first steps were to measure SUMOs and p38 mRNAs and proteins in response to H. pylori infection
A significant increase in the activated form of p38 (p-p38) was seen after shorter periods of H. pylori infection (Figure S1B and Table S1B) total p38 did not increase under these conditions
Summary
Environmental insults such as oxidative stress and hypoxia can induce the activation of the p38 mitogen activated protein kinase (MAPK) signaling pathway, causing a variety of cellular responses such as apoptosis [1,2]. p38 MAPK is activated following phosphorylation at Thr180/Tyr182 within the activation loop (p-p38), primarily by upstream MKK3 and MKK6 [3]. p38 MAPK has been shown to be distributed throughout the cytosol and nucleus [4]. Environmental insults such as oxidative stress and hypoxia can induce the activation of the p38 mitogen activated protein kinase (MAPK) signaling pathway, causing a variety of cellular responses such as apoptosis [1,2]. No nuclear translocation signals (NTSs) have been found in p38 and no nuclear carrier proteins have been identified for it. Oxidative stress and cellular apoptosis have been observed in H. pylori infected gastric tissue, which may be due to inflammation caused by overproduction of cytokines stimulated by the infection [10,11]. The p38 MAPK signaling pathway has been suggested to play a significant role in the gastric mucosal inflammatory response to chronic H. pylori infection via prostaglandin E2 [12]. The toxin Vac-A of Vac+ H. pylori strains may induce apoptosis through differential regulation of ERK1/2 and p38 MAPK [14]
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
