Format

Send to

Choose Destination
Proc Natl Acad Sci U S A. 2016 Mar 8;113(10):E1334-42. doi: 10.1073/pnas.1504555113. Epub 2016 Feb 22.

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

Author information

1
Department of Dermatology, School of Medicine, University of California, San Francisco, CA 94158; Northern California Institute for Research and Education, Veterans Affairs Medical Center, San Francisco, CA 94121;
2
Department of Biochemistry, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan;
3
Radiation Research Division, Korea Atomic Energy Research Institute, Jeongeup 580-185, Republic of Korea;
4
College of Pharmacy, Chungbuk National University, Cheongju 361-763, Republic of Korea;
5
Northern California Institute for Research and Education, Veterans Affairs Medical Center, San Francisco, CA 94121; Department of Endocrinology, School of Medicine, University of California, San Francisco, CA 94121.
6
Department of Dermatology, School of Medicine, University of California, San Francisco, CA 94158; Northern California Institute for Research and Education, Veterans Affairs Medical Center, San Francisco, CA 94121; Yoshikazu.Uchida@ucsf.edu.

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, these studies further illuminate how ER stress and S1P orchestrate critical stress-specific signals that regulate production of one protective response by stimulating production of the key innate immune element, CAMP.

KEYWORDS:

ER stress; cathelicidin; heat shock protein 90; innate immunity; sphingosine-1-phosphate

PMID:
26903652
PMCID:
PMC4791017
DOI:
10.1073/pnas.1504555113
[Indexed for MEDLINE]
Free PMC Article

Publication types, MeSH terms, Substances, Grant support

Supplemental Content

Full text links

Icon for HighWire Icon for PubMed Central
Loading ...
Support Center