TY - JOUR
T1 - Influenza virus reduces ubiquitin E3 ligase MARCH10 expression to decrease ciliary beat frequency
AU - Tsai, Mu Chun
AU - Rayner, Rachael E.
AU - Chafin, Lexie
AU - Farkas, Daniela
AU - Adair, Jessica
AU - Mishan, Chelsea
AU - Mallampalli, Rama K.
AU - Kim, Sun Hee
AU - Cormet-Boyaka, Estelle
AU - Londino, James D.
N1 - Funding Information:
This work was supported by National Institutes of Health (NIH) grants UH3HL123502, R01HL096376, R01HL097376, R01HL098174, R01HL081784, and P01HL114453 to R.K.M. It was also supported by the OSU College of Medicine Advancing Research in Infection and Immunity Pilot Award to M.T. Cure CF Columbus (C3) is supported by a Research Development Program Grant (MCCOY19R0) from the Cystic Fibrosis Foundation. This work was also supported by Grant 2021258 to M.T. from the Doris Duke Charitable Foundation through the COVID-19 Fund to Retain Clinical Scientists collaborative grant program and was made possible through the support of Grant 62288 from the John Templeton Foundation.
Publisher Copyright:
Copyright © 2023 the American Physiological Society.
PY - 2023/5
Y1 - 2023/5
N2 - Respiratory viruses, such as influenza, decrease airway cilia function and expression, which leads to reduced mucociliary clearance and inhibited overall immune defense. Ubiquitination is a posttranslational modification using E3 ligases, which plays a role in the assembly and disassembly of cilia. We examined the role of membrane-associated RING-CH (MARCH) family of E3 ligases during influenza infection and determined that MARCH10, specifically expressed in ciliated epithelial cells, is significantly decreased during influenza infection in mice, human lung epithelial cells, and human lung tissue. Cellular depletion of MARCH10 in differentiated human bronchial epithelial cells (HBECs) using CRISPR/Cas9 showed a decrease in ciliary beat frequency. Furthermore, MARCH10 cellular knockdown in combination with influenza infection selectively decreased immunoreactive levels of the ciliary component, dynein axonemal intermediate chain 1. Cellular overexpression of MARCH10 significantly decreased influenza hemagglutinin protein levels in the differentiated HBECs and knockdown of MARCH10 increased IL-1b cytokine expression, whereas overexpression had the reciprocal effect. These findings suggest that MARCH10 may have a protective role in airway pulmonary host defense and innate immunity during influenza infection.
AB - Respiratory viruses, such as influenza, decrease airway cilia function and expression, which leads to reduced mucociliary clearance and inhibited overall immune defense. Ubiquitination is a posttranslational modification using E3 ligases, which plays a role in the assembly and disassembly of cilia. We examined the role of membrane-associated RING-CH (MARCH) family of E3 ligases during influenza infection and determined that MARCH10, specifically expressed in ciliated epithelial cells, is significantly decreased during influenza infection in mice, human lung epithelial cells, and human lung tissue. Cellular depletion of MARCH10 in differentiated human bronchial epithelial cells (HBECs) using CRISPR/Cas9 showed a decrease in ciliary beat frequency. Furthermore, MARCH10 cellular knockdown in combination with influenza infection selectively decreased immunoreactive levels of the ciliary component, dynein axonemal intermediate chain 1. Cellular overexpression of MARCH10 significantly decreased influenza hemagglutinin protein levels in the differentiated HBECs and knockdown of MARCH10 increased IL-1b cytokine expression, whereas overexpression had the reciprocal effect. These findings suggest that MARCH10 may have a protective role in airway pulmonary host defense and innate immunity during influenza infection.
KW - E3 ubiquitin ligase
KW - MARCH10
KW - cilia
KW - influenza
KW - ubiquitination
UR - http://www.scopus.com/inward/record.url?scp=85153804017&partnerID=8YFLogxK
U2 - 10.1152/ajplung.00191.2022
DO - 10.1152/ajplung.00191.2022
M3 - Article
C2 - 36852930
AN - SCOPUS:85153804017
SN - 1040-0605
VL - 324
SP - L666-L676
JO - American Journal of Physiology - Lung Cellular and Molecular Physiology
JF - American Journal of Physiology - Lung Cellular and Molecular Physiology
IS - 5
ER -