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  • Orosomucoid-like 3 Supports Rhinovirus Replication in Human Epithelial Cells.

Orosomucoid-like 3 Supports Rhinovirus Replication in Human Epithelial Cells.

American journal of respiratory cell and molecular biology (2020-02-23)
Yiping Liu, Yury A Bochkov, Jens C Eickhoff, Tianchen Hu, Nicholas A Zumwalde, Jin Wen Tan, Christopher Lopez, Paul S Fichtinger, Thiruchelvi R Reddy, Katherine A Overmyer, Jennifer E Gumperz, Joshua Coon, Sameer K Mathur, James E Gern, Judith A Smith
摘要

Polymorphism at the 17q21 gene locus and wheezing responses to rhinovirus (RV) early in childhood conspire to increase the risk of developing asthma. However, the mechanisms mediating this gene-environment interaction remain unclear. In this study, we investigated the impact of one of the 17q21-encoded genes, ORMDL3 (orosomucoid-like 3), on RV replication in human epithelial cells. ORMDL3 knockdown inhibited RV-A16 replication in HeLa, BEAS-2B, A549, and NCI-H358 epithelial cell lines and primary nasal and bronchial epithelial cells. Inhibition varied by RV species, as both minor and major group RV-A subtypes RV-B52 and RV-C2 were inhibited but not RV-C15 or RV-C41. ORMDL3 siRNA did not affect expression of the major group RV-A receptor ICAM-1 or initial internalization of RV-A16. The two major outcomes of ORMDL3 activity, SPT (serine palmitoyl-CoA transferase) inhibition and endoplasmic reticulum (ER) stress induction, were further examined: silencing ORMDL3 decreased RV-induced ER stress and IFN-β mRNA expression. However, pharmacologic induction of ER stress and concomitant increased IFN-β inhibited RV-A16 replication. Conversely, blockade of ER stress with tauroursodeoxycholic acid augmented replication, pointing to an alternative mechanism for the effect of ORMDL3 knockdown on RV replication. In comparison, the SPT inhibitor myriocin increased RV-A16 but not RV-C15 replication and negated the inhibitory effect of ORMDL3 knockdown. Furthermore, lipidomics analysis revealed opposing regulation of specific sphingolipid species (downstream of SPT) by myriocin and ORMDL3 siRNA, correlating with the effect of these treatments on RV replication. Together, these data revealed a requirement for ORMDL3 in supporting RV replication in epithelial cells via SPT inhibition.

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Sigma-Aldrich
胶原蛋白 来源于人类胎盘, Bornstein and Traub Type IV, powder
Sigma-Aldrich
Myriocin from Mycelia sterilia, ≥98% (HPLC), powder
Sigma-Aldrich
MISSION® esiRNA, targeting human ORMDL3