ER stress stimulates production of the key antimicrobial peptide, cathelicidin, by forming a previously unidentified intracellular S1P signaling complex

Proceedings of the National Academy of Sciences of the United States of America
Kyungho ParkYoshikazu Uchida

Abstract

We recently identified a previously unidentified sphingosine-1-phosphate (S1P) signaling mechanism that stimulates production of a key innate immune element, cathelicidin antimicrobial peptide (CAMP), in mammalian cells exposed to external perturbations, such as UVB irradiation and other oxidative stressors that provoke subapoptotic levels of endoplasmic reticulum (ER) stress, independent of the well-known vitamin D receptor-dependent mechanism. ER stress increases cellular ceramide and one of its distal metabolites, S1P, which activates NF-κB followed by C/EBPα activation, leading to CAMP production, but in a S1P receptor-independent fashion. We now show that S1P activates NF-κB through formation of a previously unidentified signaling complex, consisting of S1P, TRAF2, and RIP1 that further associates with three stress-responsive proteins; i.e., heat shock proteins (GRP94 and HSP90α) and IRE1α. S1P specifically interacts with the N-terminal domain of heat shock proteins. Because this ER stress-initiated mechanism is operative in both epithelial cells and macrophages, it appears to be a universal, highly conserved response, broadly protective against diverse external perturbations that lead to increased ER stress. Finally, thes...Continue Reading

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Citations

Jun 30, 2016·Science Signaling·Jeffrey J Rodvold, Maurizio Zanetti
Mar 3, 2018·Cellular Microbiology·Arielle M Bryan, Maurizio Del Poeta
Aug 22, 2017·Biomolecules & Therapeutics·Chae Jin LimKyungho Park
Aug 28, 2018·Journal of Medicinal Food·Kyong-Oh ShinKyungho Park
Nov 23, 2017·Nature Reviews. Molecular Cell Biology·Yusuf A Hannun, Lina M Obeid
Jun 2, 2018·Annals of Dermatology·Sang Eun Lee, Seung Hun Lee
May 3, 2018·Frontiers in Neuroscience·Alba Di Pardo, Vittorio Maglione
Aug 21, 2019·Frontiers in Pharmacology·Sara GrassiPaola Giussani
Oct 22, 2019·Frontiers in Cell and Developmental Biology·Anika GrafenJürgen Schneider-Schaulies
Dec 22, 2019·International Journal of Molecular Sciences·Elisabetta Meacci, Mercedes Garcia-Gil
May 17, 2019·International Journal of Molecular Sciences·Yu-Ling ChangAnna Di Nardo
Jun 17, 2020·FEBS Letters·Woo-Jae Park, Joo-Won Park
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Mar 25, 2021·Diabetes/metabolism Research and Reviews·Maria Stella ValleLucia Malaguarnera
Jun 17, 2021·The EMBO Journal·Yan Lu, Dante Neculai
Jun 24, 2021·BMC Neuroscience·Kyong-Oh ShinPeter M Elias
Jun 16, 2021·Allergology International : Official Journal of the Japanese Society of Allergology·Kiyofumi Yamanishi, Yasutomo Imai
Jul 21, 2021·American Journal of Clinical Dermatology·Yoshikazu Uchida, Kyungho Park
Sep 30, 2021·Biological Reviews of the Cambridge Philosophical Society·Mengqiao CuiHongjie Zhang

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