Ndfip1 regulates itch ligase activity and airway inflammation via UbcH7

Mahesh Kathania; Minghui Zeng; Viveka Nand Yadav; Seyed Javad Moghaddam; Baoli Yang; K Venuprasad

doi:10.4049/jimmunol.1402742

Ndfip1 regulates itch ligase activity and airway inflammation via UbcH7

J Immunol. 2015 Mar 1;194(5):2160-7. doi: 10.4049/jimmunol.1402742. Epub 2015 Jan 28.

Authors

Mahesh Kathania¹, Minghui Zeng¹, Viveka Nand Yadav², Seyed Javad Moghaddam³, Baoli Yang⁴, K Venuprasad⁵

Affiliations

¹ Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 75204;
² Department of Pathology, University of Michigan, Ann Arbor, MI 48109;
³ Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; and.
⁴ Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
⁵ Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 75204; venuprasad.poojary@BaylorHealth.edu.

PMID: 25632008
DOI: 10.4049/jimmunol.1402742

Abstract

The ubiquitin-ligating enzyme (E3) Itch plays a crucial role in the regulation of inflammation, and Itch deficiency leads to severe airway inflammation. However, the molecular mechanisms by which Itch function is regulated remain elusive. In this study, we found that nontypeable Haemophilus influenzae induces the association of Itch with Ndfip1. Both Itch(-/-) and Ndfip1(-/-) mice exhibited severe airway inflammation in response to nontypeable Haemophilus influenza, which was associated with elevated expression of proinflammatory cytokines. Ndfip1 enhanced Itch ligase activity and facilitated Itch-mediated Tak1 ubiquitination. Mechanistically, Ndfip1 facilitated recruitment of ubiquitin-conjugating enzyme (E2) UbcH7 to Itch. The N-terminal region of Ndfip1 binds to UbcH7, whereas the PY motif binds to Itch. Hence, Ndfip1 acts as an adaptor for UbcH7 and Itch. Reconstitution of full-length Ndfip1 but not the mutants that fail to interact with either UbcH7 or Itch, restored the defect in Tak1 ubiquitination and inhibited elevated proinflammatory cytokine expression by Ndfip1(-/-) cells. These results provide new mechanistic insights into how Itch function is regulated during inflammatory signaling, which could be exploited therapeutically in inflammatory diseases.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Carrier Proteins / genetics
Carrier Proteins / immunology*
Carrier Proteins / metabolism
Gene Expression Regulation
Genetic Vectors
HEK293 Cells
Haemophilus Infections / genetics
Haemophilus Infections / immunology*
Haemophilus Infections / microbiology
Haemophilus influenzae / immunology
Humans
Inflammation / genetics
Inflammation / immunology
Inflammation / microbiology
Intercellular Signaling Peptides and Proteins
Lentivirus / genetics
MAP Kinase Kinase Kinases / genetics
MAP Kinase Kinase Kinases / immunology*
MAP Kinase Kinase Kinases / metabolism
Membrane Proteins / genetics
Membrane Proteins / immunology*
Membrane Proteins / metabolism
Mice
Mice, Knockout
Protein Binding
Protein Interaction Domains and Motifs
Respiratory System / immunology*
Respiratory System / metabolism
Respiratory System / microbiology
Signal Transduction
Ubiquitin-Conjugating Enzymes / genetics
Ubiquitin-Conjugating Enzymes / immunology*
Ubiquitin-Conjugating Enzymes / metabolism
Ubiquitin-Protein Ligases / genetics
Ubiquitin-Protein Ligases / immunology*
Ubiquitin-Protein Ligases / metabolism
Ubiquitination

Substances

Carrier Proteins
Intercellular Signaling Peptides and Proteins
Membrane Proteins
Ndfip1 protein, mouse
Ube2l3 protein, mouse
Ubiquitin-Conjugating Enzymes
Itch protein, mouse
Ubiquitin-Protein Ligases
MAP Kinase Kinase Kinases
MAP kinase kinase kinase 7