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ER Stress Regulator BiP and Mitochondrial Chaperone Mortalin Differentially Regulate RelA/p65 Activation and Endothelial Cell Inflammation
Author(s) -
Leonard Antony,
Rahman Arshad,
Fazal Fabeha
Publication year - 2013
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.27.1_supplement.1131.7
Subject(s) - inflammation , unfolded protein response , microbiology and biotechnology , endoplasmic reticulum , phosphorylation , biology , gene knockdown , regulator , cancer research , chemistry , apoptosis , immunology , biochemistry , gene
ER stress and mitochondrial dysfunction is implicated in the pathogenesis of neurological disorders, metabolic diseases, and more recently inflammatory conditions. Endothelial cell (EC) inflammation is an important component of many inflammatory diseases including acute lung injury (ALI). Here, we show that endoplasmic reticulum (ER) stress regulator BiP and mitochondrial chaperone mortalin differentially regulate NF‐κB to cause EC inflammation. RNAi knockdown of BiP or mortalin, each impaired thrombin‐induced NFκB‐transcriptional activity and expression of ICAM‐1 and VCAM‐1 in EC. Further analysis revealed that the inhibitory effect of BiP depletion on these responses was due to blockade of phosphorylation/degradation of IκBα, serine 536 phosphorylation, nuclear translocation and DNA binding of RelA/p65. By contrast, depletion of mortalin had no effect on the above responses, raising the possibility that mortalin may mediate NFκB activity by regulating the nuclear events such as acetylation/methylation of RelA/p65 and/or chromatin remodeling. These results identify BiP and Mthsp75 as novel mediators of EC inflammation that may act in concert to regulate cytosolic and nuclear events to promote NF‐κB activity. Importantly, these data also reveal mechanistic links between ER stress, mitochondrial dysfunction and EC inflammation. (Supported by NIH HL096907)