Myeloid-associated differentiation marker is a novel SP-A-associated transmembrane protein whose expression on airway epithelial cells correlates with asthma severity

Abstract

Surfactant protein A (SP-A) is well-known for its protective role in pulmonary immunity. Previous studies from our group have shown that SP-A mediates eosinophil activities, including degranulation and apoptosis. In order to identify potential binding partners on eosinophils for SP-A, eosinophil lysates were subjected to SP-A pull-down and tandem mass spectrometry (MS/MS) analysis. We identified one membrane-bound protein, myeloid-associated differentiation marker (MYADM), as a candidate SP-A binding partner. Blocking MYADM on mouse and human eosinophils ex vivo prevented SP-A from inducing apoptosis; blocking MYADM in vivo led to increased persistence of eosinophilia and airway hyper-responsiveness in an ovalbumin (OVA) allergy model and increased airways resistance and mucus production in a house dust mite (HDM) asthma model. Examination of a subset of participants in the Severe Asthma Research Program (SARP) cohort revealed a significant association between epithelial expression of MYADM in asthma patients and parameters of airway inflammation, including: peripheral blood eosinophilia, exhaled nitric oxide (FeNO) and the number of exacerbations in the past 12 months. Taken together, our studies provide the first evidence of MYADM as a novel SP-A-associated protein that is necessary for SP-A to induce eosinophil apoptosis and we bring to light the potential importance of this previously unrecognized transmembrane protein in patients with asthma.

Small Peptide Derivatives Within the Carbohydrate Recognition Domain of SP-A2 Modulate Asthma Outcomes in Mouse Models and Human Cells

“…SP-A induces eosinophil apoptosis which is in line with the reduced eosinophilia detected in the peptide treated mice in the HDM model (22). Furthermore, SP-A works through a newly discovered receptor on eosinophils for this activity, MYADM, which may also be the therapeutic target for the peptides in the HDM model (27). SP-A works directly on epithelial cells to reduce STAT-3 signaling, which may also be true of the SP-A peptides, however additional testing is needed (4).…”

Detecting macroevolutionary genotype–phenotype associations using error-corrected rates of protein convergence

“…The expression evolution was coupled with convergent substitutions in the protein sites corresponding to the substrate-binding pocket of the de-ADP-ribosylating homolog NUDT16 (Thirawatananond et al, 2019;Zhang et al, 2020). Protein convergence linked to testis-specific expression was also observed in myeloid-associated differentiation marker (MYADM), which encodes a transmembrane protein that localizes to membrane rafts (Aranda et al, 2011), regulates eosinophil apoptosis through binding to Surfactant protein A (SP-A) (Dy et al, 2021), and participates in cell proliferation and migration (Sun et al, 2016). This orthogroup showed joint convergence in two pairs of branches, in both of which the convergent amino acid substitutions were almost entirely confined to one side of the transmembrane domains (Fig.…”

The MAL Family of Proteins: Normal Function, Expression in Cancer, and Potential Use as Cancer Biomarkers

“…MYADM has been implicated in atherosclerotic disease and hypertension as a target of miR-182 [61][62][63], which was previously found to modulate human smooth muscle cell differentiation, proliferation, and migration [63]. It is also known to be relevant to asthma severity as a candidate partner of surfactant protein (SP)-A [64], a protein secreted by alveolar type 2 cells that protects the lung by enhancing the clearance of microbes and modulating the inflammatory response [65]. A homozygous deletion affecting MY-ADML2 was found in a consanguineous family with an unusual combination of skeletal abnormalities.…”