tetano
Editor, Senior Moderator
Am J Physiol Lung Cell Mol Physiol. 2013 Mar 1. [Epub ahead of print]
Influenza Matrix Protein 2 Alters CFTR Expression and Function through its Ion Channel Activity.
Londino JD, Lazrak A, Jurkuvenaite A, Collawn JF, Noah JW, Matalon S.
Source
1University of Alabama at Birmingham.
Abstract
The human cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic AMP-activated chloride (Cl-) channel in the lung epithelium that helps regulate the thickness and composition of the lung epithelial lining fluid. We investigated whether influenza M2 protein, a pH-activated proton (H+) channel that traffics to the plasma membrane of infected cells, altered CFTR expression and function. M2 decreased CFTR activity in: (1) Xenopus oocytes injected with human CFTR; (2) epithelial cells (HEK-293) stably transfected with CFTR; (3) human bronchial epithelial cells (16HBE14o-) expressing native CFTR. This inhibition was partially reversed by an inhibitor of the ubiquitin-activating enzyme E1. Next we investigated whether the M2 inhibition of CFTR activity was due to an increase of secretory organelle pH by M2. Incubation of Xenopus oocytes expressing CFTR with ammonium chloride or concanamycin A, two agents which alkalinize the secretory pathway, inhibited CFTR activity in a dose-dependent manner. Treatment of M2 and CFTR expressing oocytes with the M2 ion channel inhibitor amantadine prevented the loss in CFTR expression and activity; in addition M2 mutants, lacking the ability to transport H+, did not alter CFTR activity in Xenopus oocytes and HEK cells. Expression of a M2 mutant retained in the endoplasmic reticulum also failed to alter CFTR activity. In summary, our data show that M2 decreases CFTR activity by increasing secretory organelle pH which targets CFTR for destruction by the ubiquitin system. Alteration of CFTR activity has important consequences for fluid regulation and may potentially modify the immune response to viral infection.
PMID:
23457187
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/23457187
Influenza Matrix Protein 2 Alters CFTR Expression and Function through its Ion Channel Activity.
Londino JD, Lazrak A, Jurkuvenaite A, Collawn JF, Noah JW, Matalon S.
Source
1University of Alabama at Birmingham.
Abstract
The human cystic fibrosis transmembrane conductance regulator (CFTR) is a cyclic AMP-activated chloride (Cl-) channel in the lung epithelium that helps regulate the thickness and composition of the lung epithelial lining fluid. We investigated whether influenza M2 protein, a pH-activated proton (H+) channel that traffics to the plasma membrane of infected cells, altered CFTR expression and function. M2 decreased CFTR activity in: (1) Xenopus oocytes injected with human CFTR; (2) epithelial cells (HEK-293) stably transfected with CFTR; (3) human bronchial epithelial cells (16HBE14o-) expressing native CFTR. This inhibition was partially reversed by an inhibitor of the ubiquitin-activating enzyme E1. Next we investigated whether the M2 inhibition of CFTR activity was due to an increase of secretory organelle pH by M2. Incubation of Xenopus oocytes expressing CFTR with ammonium chloride or concanamycin A, two agents which alkalinize the secretory pathway, inhibited CFTR activity in a dose-dependent manner. Treatment of M2 and CFTR expressing oocytes with the M2 ion channel inhibitor amantadine prevented the loss in CFTR expression and activity; in addition M2 mutants, lacking the ability to transport H+, did not alter CFTR activity in Xenopus oocytes and HEK cells. Expression of a M2 mutant retained in the endoplasmic reticulum also failed to alter CFTR activity. In summary, our data show that M2 decreases CFTR activity by increasing secretory organelle pH which targets CFTR for destruction by the ubiquitin system. Alteration of CFTR activity has important consequences for fluid regulation and may potentially modify the immune response to viral infection.
PMID:
23457187
[PubMed - as supplied by publisher]
http://www.ncbi.nlm.nih.gov/pubmed/23457187