title: The E3 ubiquitin ligase midline 1 promotes allergen and rhinovirus-induced asthma by inhibiting protein phosphatase 2A activity.
abstract: Allergic airway inflammation is associated with activation of innate immune pathways by allergens. Acute exacerbations of asthma are commonly associated with rhinovirus infection. Here we show that, after exposure to house dust mite (HDM) or rhinovirus infection, the E3 ubiquitin ligase midline 1 (MID1) is upregulated in mouse bronchial epithelium. HDM regulates MID1 expression in a Toll-like receptor 4 (TLR4)- and tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-dependent manner. MID1 decreases protein phosphatase 2A (PP2A) activity through association with its catalytic subunit PP2Ac. siRNA-mediated knockdown of MID1 or pharmacological activation of PP2A using a nonphosphorylatable FTY720 analog in mice exposed to HDM reduces airway hyperreactivity and inflammation, including the expression of interleukin-25 (IL-25), IL-33 and CCL20, IL-5 and IL-13 release, nuclear factor (NF)κB activity, p38 mitogen-activated protein kinase (MAPK) phosphorylation, accumulation of eosinophils, T lymphocytes and myeloid dendritic cells, and the number of mucus-producing cells. MID1 inhibition also limited rhinovirus-induced exacerbation of allergic airway disease. We found that MID1 was upregulated in primary human bronchial epithelial cells upon HDM or rhinovirus exposure, and this correlated with TRAIL and CCL20 expression. Together, these findings identify a key role of MID1 in allergic airway inflammation and links innate immune pathway activation to the development and exacerbation of asthma.
authors: Experimental and Translational Respiratory Group, University of Newcastle and Hunter Medical Research Institute, Newcastle, New South Wales, Australia.
authors: Adam
authors: A
authors: Collison
authors: Luke
authors: L
authors: Hatchwell
authors: Nicole
authors: N
authors: Verrills
authors: Peter A B
authors: PA
authors: Wark
authors: Ana Pereira
authors: AP
authors: de Siqueira
authors: Melinda
authors: M
authors: Tooze
authors: Helen
authors: H
authors: Carpenter
authors: Anthony S
authors: AS
authors: Don
authors: Jonathan C
authors: JC
authors: Morris
authors: Nives
authors: N
authors: Zimmermann
authors: Nathan W
authors: NW
authors: Bartlett
authors: Marc E
authors: ME
authors: Rothenberg
authors: Sebastian L
authors: SL
authors: Johnston
authors: Paul S
authors: PS
authors: Foster
authors: Joerg
authors: J
authors: Mattes
mesh_terms: D000485:Allergens / Q000276:immunology*; D000818:Animals; D001249:Asthma / Q000209:etiology*; D002478:Cells, Cultured; D006801:Humans; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008868:Microtubule Proteins / Q000502:physiology*; D009687:Nuclear Proteins / Q000502:physiology*; D010850:Picornaviridae Infections / Q000150:complications*; D054648:Protein Phosphatase 2 / Q000037:antagonists & inhibitors*; D011506:Proteins / Q000502:physiology*; D012229:Rhinovirus; D014157:Transcription Factors / Q000502:physiology*; D044767:Ubiquitin-Protein Ligases / Q000502:physiology*
chemical_list: D000485:Allergens; D008868:Microtubule Proteins; D009687:Nuclear Proteins; D011506:Proteins; D014157:Transcription Factors; C109052:MID1 protein, human; C109037:Mid1 protein, mouse; D044767:Ubiquitin-Protein Ligases; D054648:Protein Phosphatase 2