期刊
CELL CALCIUM
卷 100, 期 -, 页码 -出版社
ELSEVIER SCI LTD
DOI: 10.1016/j.ceca.2021.102477
关键词
Mannan-binding lectin; Endoplasmic reticulum stress; Calcium; Liver injury; Inositol 1; 4; 5-trisphosphate receptor
类别
资金
- National Natural Science Foundation of China [82171745, 82071781, 81971550, and81873872]
- Science and Technology Planning Project of Guangzhou [202002030160]
- Innovation team of chronic kidney disease with integrated traditional Chinese and Western Medicine [2019KCXTD014]
MBL plays a critical role in ER calcium homeostasis and stress response, with its deficiency exacerbating liver injury susceptibility to ER stress. This study reveals a novel function of MBL in regulating ER stress and provides new insights into liver injury associated with MBL deficiency.
The aberrant release of endoplasmic reticulum (ER) calcium leads to the disruption of intracellular calcium homeostasis, which is associated with the occurrence of ER stress and closely related to the pathogenesis of liver damage. Mannan-binding lectin (MBL) is a soluble calcium-dependent protein synthesized primarily in hepatocytes and is a pattern recognition molecule in the innate immune system. MBL deficiency is highly prevalent in the population and has been reported to be associated with susceptibility to several liver diseases. We here showed that genetic MBL ablation strongly sensitized mice to ER stress-induced liver injury. Mechanistic studies established that MBL directly interacted with ER-resident chaperone immunoglobulin heavy chain binding protein (BiP), and MBL deficiency accelerated the separation of PKR-like ER kinase (PERK) from BiP during hepatic ER stress. Moreover, MBL deficiency led to enhanced activation of the PERK-C/EBP-homologous protein (CHOP) pathway and initiates an inositol 1,4,5-trisphosphate receptor (IP3R)-mediated calcium release from the ER, thereby aggravating the hepatic ER stress response. Our results demonstrate an unexpected function of MBL in ER calcium homeostasis and ER stress response, thus providing new insight into the liver injury related to ER stress in patients with MBL deficiency.
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