NDLI: LRRC8A channels support TNF -induced superoxide production by Nox1 which is required for receptor endocytosis.

Content Provider	World Health Organization (WHO)-Global Index Medicus
Author	Choi, Hyehun Ettinger, Nicholas Rohrbough, Jeffrey Dikalova, Anna Nguyen, Hong N. Lamb, Fred S.
Description	Country affiliation: United States Author Affiliation: Choi H ( Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, United States.); Ettinger N ( Department of Pediatrics, Baylor College of Medicine, Houston, TX 77030, United States.); Rohrbough J ( Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, United States.); Dikalova A ( Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, United States.); Nguyen HN ( Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, United States.); Lamb FS ( Department of Pediatrics, Vanderbilt University Medical Center, Nashville, TN 37232, United States. Electronic address: fred.s.lamb@vanderbilt.edu.)
Abstract	Leucine Rich Repeat Containing 8A (LRRC8A) is a required component of volume-regulated anion channels (VRACs). In vascular smooth muscle cells, tumor necrosis factor- (TNF ) activates VRAC via type 1 TNF receptors (TNFR1), and this requires superoxide (O ) production by NADPH oxidase 1 (Nox1). VRAC inhibitors suppress the inflammatory response to TNF by an unknown mechanism. We hypothesized that LRRC8A directly supports Nox1 activity, providing a link between VRAC current and inflammatory signaling. VRAC inhibition by 4-(2-butyl-6,7-dichlor-2-cyclopentylindan-1-on-5-yl) oxobutyric acid (DCPIB) impaired NF-κB activation by TNF . LRRC8A siRNA reduced the magnitude of VRAC and inhibited TNF -induced NF-κB activation, iNOS and VCAM expression, and proliferation of VSMCs. Signaling steps disrupted by both siLRRC8A and DCPIB included; extracellular O production by Nox1, c-Jun N-terminal kinase (JNK) phosphorylation and endocytosis of TNFR1. Extracellular superoxide dismutase, but not catalase, selectively inhibited TNFR1 endocytosis and JNK phosphorylation. Thus, O is the critical extracellular oxidant for TNFR signal transduction. Reducing JNK expression (siJNK) increased extracellular O suggesting that JNK provides important negative feedback regulation to Nox1 at the plasma membrane. LRRC8A co-localized by immunostaining, and co-immunoprecipitated with, both Nox1 and its p22phox subunit. LRRC8A is a component of the Nox1 signaling complex. It is required for extracellular O production, which is in turn essential for TNFR1 endocytosis. These data are the first to provide a molecular mechanism for the potent anti-proliferative and anti-inflammatory effects of VRAC inhibition.
File Format	HTM / HTML
ISSN	08915849
Journal	Free Radical Biology and Medicine
Volume Number	101
e-ISSN	18734596
Language	English
Publisher	Elsevier
Publisher Date	2016-12-01
Publisher Place	United States
Access Restriction	One Nation One Subscription (ONOS)
Content Type	Text
Resource Type	Article
Subject	Physiology (medical) Biochemistry

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