Epithelial STAT6 O-GlcNAcylation drives a concerted anti-helminth alarmin response dependent on tuft cell hyperplasia and Gasdermin C.
Acylation
Alarmins
/ immunology
Anthelmintics
/ immunology
Biomarkers, Tumor
Cytokines
DNA-Binding Proteins
Helminthiasis
/ immunology
Humans
Hyperplasia
Inflammation
Interleukin-33
Intestinal Mucosa
/ immunology
Mebendazole
N-Acetylglucosaminyltransferases
/ immunology
Pore Forming Cytotoxic Proteins
STAT6 Transcription Factor
/ immunology
Gasdermin
IL-10
IL-25
IL-33
O-GlcNAc
OGT
STAT6
Tuft cell
colitis
goblet cell
Journal
Immunity
ISSN: 1097-4180
Titre abrégé: Immunity
Pays: United States
ID NLM: 9432918
Informations de publication
Date de publication:
12 04 2022
12 04 2022
Historique:
received:
26
08
2021
revised:
25
01
2022
accepted:
14
03
2022
pubmed:
7
4
2022
medline:
16
4
2022
entrez:
6
4
2022
Statut:
ppublish
Résumé
The epithelium is an integral component of mucosal barrier and host immunity. Following helminth infection, the intestinal epithelial cells secrete "alarmin" cytokines, such as interleukin-25 (IL-25) and IL-33, to initiate the type 2 immune responses for helminth expulsion and tolerance. However, it is unknown how helminth infection and the resulting cytokine milieu drive epithelial remodeling and orchestrate alarmin secretion. Here, we report that epithelial O-linked N-Acetylglucosamine (O-GlcNAc) protein modification was induced upon helminth infections. By modifying and activating the transcription factor STAT6, O-GlcNAc transferase promoted the transcription of lineage-defining Pou2f3 in tuft cell differentiation and IL-25 production. Meanwhile, STAT6 O-GlcNAcylation activated the expression of Gsdmc family genes. The membrane pore formed by GSDMC facilitated the unconventional secretion of IL-33. GSDMC-mediated IL-33 secretion was indispensable for effective anti-helminth immunity and contributed to induced intestinal inflammation. Protein O-GlcNAcylation can be harnessed for future treatment of type 2 inflammation-associated human diseases.
Identifiants
pubmed: 35385697
pii: S1074-7613(22)00132-7
doi: 10.1016/j.immuni.2022.03.009
pmc: PMC9109499
mid: NIHMS1791543
pii:
doi:
Substances chimiques
Alarmins
0
Anthelmintics
0
Biomarkers, Tumor
0
Cytokines
0
DNA-Binding Proteins
0
GSDMC protein, human
0
Interleukin-33
0
Pore Forming Cytotoxic Proteins
0
STAT6 Transcription Factor
0
STAT6 protein, human
0
Mebendazole
81G6I5V05I
N-Acetylglucosaminyltransferases
EC 2.4.1.-
O-GlcNAc transferase
EC 2.4.1.-
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
623-638.e5Subventions
Organisme : NIAID NIH HHS
ID : R01 AI139420
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK122056
Pays : United States
Organisme : NIAID NIH HHS
ID : R21 AI140109
Pays : United States
Organisme : NIAID NIH HHS
ID : R56 AI162791
Pays : United States
Commentaires et corrections
Type : CommentIn
Type : ErratumIn
Informations de copyright
Copyright © 2022 Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors disclose no conflicts.
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