Orosomucoid-like 3 Supports Rhinovirus Replication in Human Epithelial Cells

Autor: Jin Wen Tan, Joshua J. Coon, Thiruchelvi R. Reddy, Yury A. Bochkov, Katherine A. Overmyer, Yi-Ping Liu, Christopher Lopez, Paul S. Fichtinger, Jennifer E Gumperz, James E. Gern, Jens C. Eickhoff, Nicholas A Zumwalde, Tianchen Hu, Sameer K. Mathur, Judith A. Smith
Rok vydání: 2020
Předmět:
0301 basic medicine
Pulmonary and Respiratory Medicine
Genotype
Rhinovirus
media_common.quotation_subject
Clinical Biochemistry
Serine C-Palmitoyltransferase
Bronchi
Virus Replication
Fatty Acids
Monounsaturated
Taurochenodeoxycholic Acid
03 medical and health sciences
chemistry.chemical_compound
0302 clinical medicine
Myriocin
Humans
Gene silencing
Genetic Predisposition to Disease
RNA
Small Interfering
Internalization
Molecular Biology
Gene
Cells
Cultured
media_common
Sphingolipids
Gene knockdown
Picornaviridae Infections
Chemistry
Endoplasmic reticulum
Editorials
Membrane Proteins
Epithelial Cells
Interferon-beta
Cell Biology
Endoplasmic Reticulum Stress
Sphingolipid
Asthma
Recombinant Proteins
Cell biology
Nasal Mucosa
030104 developmental biology
030228 respiratory system
A549 Cells
Unfolded protein response
RNA Interference
Chromosomes
Human
Pair 17
HeLa Cells
Zdroj: American Journal of Respiratory Cell and Molecular Biology
ISSN: 1535-4989
1044-1549
DOI: 10.1165/rcmb.2019-0237oc
Popis: 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.
Databáze: OpenAIRE
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