Pharmaceutical Sciences Faculty Publications

Title

SASH1 Is a Scaffold Molecule in Endothelial TLR4 Signaling

Document Type

Article

Publication Date

7-15-2013

Journal Title

Journal of Immunology

ISSN

1550-6606

Volume

191

Issue

2

First Page

892

Last Page

901

DOI

10.4049/jimmunol.1200583

PubMed ID

23776175

Abstract

Recognition of microbial products by TLRs is critical for mediating innate immune responses to invading pathogens. In this study, we identify a novel scaffold protein in TLR4 signaling called SAM and SH3 domain containing protein 1 (SASH1). Sash1 is expressed across all microvascular beds and functions as a scaffold molecule to independently bind TRAF6, TAK1, IκB kinase α, and IκB kinase β. This interaction fosters ubiquitination of TRAF6 and TAK1 and promotes LPS-induced NF-κB, JNK, and p38 activation, culminating in increased production of proinflammatory cytokines and increased LPS-induced endothelial migration. Our findings suggest that SASH1 acts to assemble a signaling complex downstream of TLR4 to activate early endothelial responses to receptor activation.

Keywords

Endothelial cells, enzyme activation, immunity, innate, lipopolysaccharides, RNA interference, signal transduction, tumor suppressor proteins

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