Journal
SCIENCE CHINA-LIFE SCIENCES
Volume 61, Issue 10, Pages 1222-1232Publisher
SCIENCE PRESS
DOI: 10.1007/s11427-018-9339-0
Keywords
cholesterol transport; NF-kappa B2; NPC2; transcriptional regulation
Categories
Funding
- National Natural Science Foundation of China [91754102, 31771568, 31701030, 31601147, 31600651]
- 111 Project of Ministry of Education of China [B16036]
- Natural Science Foundation of Hubei Province [2016CFA012]
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Niemann-Pick type C2 (NPC2) is a lysosome luminal protein that functions in concert with NPC1 to mediate egress of low-density lipoprotein-derived cholesterol from lysosome. The nuclear factor kappa B subunit 2 (NF-B2) protein is a component of NF-B transcription factor complex critically implicated in immune and inflammatory responses. Here, we report that NF-B2 regulates intracellular cholesterol transport by controlling NPC2 expression. RNAi-mediated disruption of NF-B2, as well as other signaling members of the non-canonical NF-B pathway, caused intracellular cholesterol accumulation. Blockage of the non-canonical NF-B pathway suppressed NPC2 expression, whereas Lymphotoxin receptor (LTR) activation or Baff receptor (BaffR) stimulation up-regulated the mRNA abundance and protein level of NPC2. Further, NF-B2 activated NPC2 transcription through direct binding to its promoter region. We also observed cholesterol accumulation in NF-B2-deficient zebrafish embryo and NF-B2 mutant mice. Collectively, these data identify a regulatory role for the non-canonical NF-B pathway in intracellular cholesterol trafficking and suggest a link between cholesterol transport and immune system.
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