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Tribbles pseudokinase NIPI-3 regulates intestinal immunity in Caenorhabditis elegans by controlling SKN-1/Nrf activity.
Cell Rep. 2021 08 17; 36(7):109529.CR

Abstract

In Caenorhabditis elegans, ROS generated in response to intestinal infection induces SKN-1, a protective transcription factor homologous to nuclear factor erythroid 2-related factor 1 or 2 (NRF1/2) in mammals. Many factors regulate SKN-1, including the p38 mitogen-activated protein kinase (MAPK) cascade that activates SKN-1 by phosphorylation. In this work, another positive regulator of SKN-1 is identified: NIPI-3, a Tribbles pseudokinase. NIPI-3 has been reported to protect against intestinal infection by negatively regulating the CCAT enhancer binding protein (C/EBP) bZIP transcription factor CEBP-1. Here we demonstrate that CEBP-1 positively regulates the vhp-1 transcript, which encodes a phosphatase that dephosphorylates the p38 MAPK called PMK-1. The increased levels of VHP-1 caused by CEBP-1 transcriptional enhancement result in less PMK-1 phosphorylation, affecting SKN-1 activity and intestinal resistance to the pathogen. The data support a model in which NIPI-3's negative regulation of CEBP-1 decreases VHP-1 phosphatase activity, allowing increased stimulation of SKN-1 activity by the p38 MAPK phosphorylation cascade in the intestine.

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Authors+Show Affiliations

Wu C
Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Karakuzu O
Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA.
Garsin DA
Department of Microbiology and Molecular Genetics, The University of Texas Health Science Center at Houston, Houston, TX 77030, USA. Electronic address: danielle.a.garsin@uth.tmc.edu.

MeSH

AnimalsCaenorhabditis elegansCaenorhabditis elegans ProteinsDNA-Binding ProteinsFeedback, PhysiologicalGene Expression RegulationImmunity, InnateIntestinesProtein KinasesTranscription Factors

Pub Type(s)

Journal Article
Research Support, N.I.H., Extramural

Language

eng

PubMed ID

34407394

Citation

Wu, Chenggang, et al. "Tribbles Pseudokinase NIPI-3 Regulates Intestinal Immunity in Caenorhabditis Elegans By Controlling SKN-1/Nrf Activity." Cell Reports, vol. 36, no. 7, 2021, p. 109529.
Wu C, Karakuzu O, Garsin DA. Tribbles pseudokinase NIPI-3 regulates intestinal immunity in Caenorhabditis elegans by controlling SKN-1/Nrf activity. Cell Rep. 2021;36(7):109529.
Wu, C., Karakuzu, O., & Garsin, D. A. (2021). Tribbles pseudokinase NIPI-3 regulates intestinal immunity in Caenorhabditis elegans by controlling SKN-1/Nrf activity. Cell Reports, 36(7), 109529. https://doi.org/10.1016/j.celrep.2021.109529
Wu C, Karakuzu O, Garsin DA. Tribbles Pseudokinase NIPI-3 Regulates Intestinal Immunity in Caenorhabditis Elegans By Controlling SKN-1/Nrf Activity. Cell Rep. 2021 08 17;36(7):109529. PubMed PMID: 34407394.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Tribbles pseudokinase NIPI-3 regulates intestinal immunity in Caenorhabditis elegans by controlling SKN-1/Nrf activity. AU - Wu,Chenggang, AU - Karakuzu,Ozgur, AU - Garsin,Danielle A, PY - 2021/04/19/received PY - 2021/06/23/revised PY - 2021/07/22/accepted PY - 2021/8/18/entrez PY - 2021/8/19/pubmed PY - 2022/2/10/medline KW - C. elegans KW - NIPI-3 KW - Nrf KW - ROS KW - SKN-1 KW - Tribbles pseudokinase KW - bZIP KW - bacterial pathogenesis KW - innate immunity KW - p38 MAPK SP - 109529 EP - 109529 JF - Cell reports JO - Cell Rep VL - 36 IS - 7 N2 - In Caenorhabditis elegans, ROS generated in response to intestinal infection induces SKN-1, a protective transcription factor homologous to nuclear factor erythroid 2-related factor 1 or 2 (NRF1/2) in mammals. Many factors regulate SKN-1, including the p38 mitogen-activated protein kinase (MAPK) cascade that activates SKN-1 by phosphorylation. In this work, another positive regulator of SKN-1 is identified: NIPI-3, a Tribbles pseudokinase. NIPI-3 has been reported to protect against intestinal infection by negatively regulating the CCAT enhancer binding protein (C/EBP) bZIP transcription factor CEBP-1. Here we demonstrate that CEBP-1 positively regulates the vhp-1 transcript, which encodes a phosphatase that dephosphorylates the p38 MAPK called PMK-1. The increased levels of VHP-1 caused by CEBP-1 transcriptional enhancement result in less PMK-1 phosphorylation, affecting SKN-1 activity and intestinal resistance to the pathogen. The data support a model in which NIPI-3's negative regulation of CEBP-1 decreases VHP-1 phosphatase activity, allowing increased stimulation of SKN-1 activity by the p38 MAPK phosphorylation cascade in the intestine. SN - 2211-1247 UR - https://www.unboundmedicine.com/medline/citation/34407394/Tribbles_pseudokinase_NIPI_3_regulates_intestinal_immunity_in_Caenorhabditis_elegans_by_controlling_SKN_1/Nrf_activity_ DB - PRIME DP - Unbound Medicine ER -