title: Ndfip1 regulates itch ligase activity and airway inflammation via UbcH7.
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.
authors: Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 75204;
authors: Mahesh
authors: M
authors: Kathania
authors: Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 75204;
authors: Minghui
authors: M
authors: Zeng
authors: Department of Pathology, University of Michigan, Ann Arbor, MI 48109;
authors: Viveka Nand
authors: VN
authors: Yadav
authors: Pulmonary Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030; and.
authors: Seyed Javad
authors: SJ
authors: Moghaddam
authors: Department of Obstetrics and Gynecology, Carver College of Medicine, University of Iowa, Iowa City, IA 52242.
authors: Baoli
authors: B
authors: Yang
authors: Baylor Institute for Immunology Research, Baylor Research Institute, Dallas, TX 75204; venuprasad.poojary@BaylorHealth.edu.
authors: K
authors: K
authors: Venuprasad
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D005786:Gene Expression Regulation; D005822:Genetic Vectors; D057809:HEK293 Cells; D006192:Haemophilus Infections / Q000235:genetics / Q000276:immunology* / Q000382:microbiology; D006193:Haemophilus influenzae / Q000276:immunology; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000382:microbiology; D036341:Intercellular Signaling Peptides and Proteins; D016086:Lentivirus / Q000235:genetics; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D012137:Respiratory System / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology; D015398:Signal Transduction; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D054875:Ubiquitination; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D002352:Carrier Proteins; D036341:Intercellular Signaling Peptides and Proteins; D020930:MAP Kinase Kinase Kinases; D008565:Membrane Proteins; D044763:Ubiquitin-Conjugating Enzymes; D044767:Ubiquitin-Protein Ligases; D000099151:MAP Kinase Kinase Kinase 7; C499188:Ndfip1 protein, mouse; C117188:Ube2l3 protein, mouse; C471637:Itch protein, mouse