Open AccessMycobacterial lipoprotein activates autophagy via TLR2/1/CD14 and a functional vitamin D receptor signalling
Author(s) -
Shin DongMin,
Yuk JaeMin,
Lee HyeMi,
Lee SangHee,
Son Ji Woong,
Harding Clifford V.,
Kim JinMan,
Modlin Robert L.,
Jo EunKyeong
Publication year - 2010
Publication title -
cellular microbiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.542
H-Index - 138
eISSN - 1462-5822
pISSN - 1462-5814
DOI - 10.1111/j.1462-5822.2010.01497.x
Subject(s) - autophagy , microbiology and biotechnology , biology , ampk , tlr2 , calcitriol receptor , p38 mitogen activated protein kinases , cathelicidin , protein kinase a , cd14 , mapk/erk pathway , becn1 , signal transduction , kinase , receptor , innate immune system , biochemistry , tlr4 , apoptosis
Summary In human monocytes, Toll‐like receptor (TLR) 2/1 activation leads to vitamin D3‐dependent antimycobacterial activities, but the molecular mechanisms by which TLR2/1 stimulation induces antimicrobial activities against mycobacteria remain unclear. Here we show that TLR2/1/CD14 stimulation by mycobacterial lipoprotein LpqH can robustly activate antibacterial autophagy through vitamin D receptor signalling activation and cathelicidin induction. We found that CCAAT/enhancer‐binding protein (C/EBP)‐β‐dependent induction of 25‐hydroxycholecalciferol‐1α‐hydroxylase (Cyp27b1) hydroxylase was critical for LpqH‐induced cathelicidin expression and autophagy. In addition, increases in intracellular calcium following AMP‐activated protein kinase (AMPK) activation played a crucial role in LpqH‐induced autophagy. Moreover, AMPK‐dependent p38 mitogen‐activated protein kinase (MAPK) activation was required for LpqH‐induced Cyp27b1 expression and autophagy activation. Collectively, these data suggest that TLR2/1/CD14‐Ca 2+ ‐AMPK‐p38 MAPK pathways contribute to C/EBP‐β‐dependent expression of Cyp27b1 and cathelicidin, which played an essential role in LpqH‐induced autophagy. Furthermore, these results establish a previously uncharacterized signalling pathway of antimycobacterial host defence through a functional link of TLR2/1/CD14‐dependent sensing to the induction of autophagy.