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Lipopolysaccharide-induced activation of NF-κB non-canonical pathway requires BCL10 serine 138 and NIK phosphorylations.

Abstract：

BACKGROUND AND AIMS:B-cell lymphoma/leukemia (BCL)-10 and reactive oxygen species mediate two pathways of NF-κB (RelA) activation by lipopolysaccharide (LPS) in human colonic epithelial cells. The pathway for LPS activation of RelB by the non-canonical pathway (RelB) in non-myeloid cells was not yet reported, but important for understanding the range of potential microbial LPS-induced effects in inflammatory bowel disease. METHODS:Experiments were performed in human colonic epithelial cells and in mouse embryonic fibroblasts deficient in components of the IkappaB kinase (IKK) signalosome, in order to detect mediators of the non-canonical pathway of NF-κB activation, including nuclear RelB and p52 and phospho- and total NF-κB inducing kinase (NIK). BCL10 was silenced by siRNA and effects of mutations of specific phosphorylation sites of BCL10 (Ser138Gly and Ser218Gly) were determined. RESULTS:By the non-canonical pathway, LPS exposure increased nuclear RelB and p52, and phospho-NIK, with no change in total NIK. Phosphorylation of BCL10 serine 138 was required for NIK phosphorylation, since mutation of this residue eliminated the increases in phospho-NIK and nuclear RelB and p52. Mutations of either serine 138 or serine 218 reduced RelA, p50, and phospho-IκBα of the canonical pathway. Effects of LPS stimulation and BCL10 silencing on NIK phosphorylation were demonstrated in confocal images. CONCLUSIONS:LPS induces activation of both canonical and non-canonical pathways of NF-κB in human colonic epithelial cells, and the non-canonical pathway requires phosphorylations of BCL10 (serine 138) and NIK. These findings demonstrate the important role of BCL10 in mediating LPS-induced inflammation in human colonic epithelial cells and may open new avenues for therapeutic interventions.

journal_name

Exp Cell Res

journal_title

Experimental cell research

authors

Bhattacharyya S,Borthakur A,Dudeja PK,Tobacman JK

doi

10.1016/j.yexcr.2010.05.004

subject

Has Abstract

pub_date

2010-11-15 00:00:00

pages

3317-27

issue

eissn

0014-4827

issn

1090-2422

pii

S0014-4827(10)00209-0

journal_volume

316

pub_type

杂志文章

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Lipopolysaccharide-induced activation of NF-κB non-canonical pathway requires BCL10 serine 138 and NIK phosphorylations.