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HPS1 Regulates the Maturation of Large Dense Core Vesicles and Lysozyme Secretion in Paneth Cells

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机构: [1]Capital Med Univ, Genet & Birth Defects Control Ctr,Beijing Pediat, Beijing Childrens Hosp,MOE Key Lab Major Dis Chil, Natl Ctr Childrens Hlth,Beijing Key Lab Genet Bir, Beijing, Peoples R China [2]Univ Chinese Acad Sci, Chinese Acad Sci, Inst Genet & Dev Biol, Beijing, Peoples R China [3]Capital Med Univ, Beijing Tongren Hosp, Dept Dermatol, Beijing, Peoples R China [4]Tsinghua Univ, Inst Immunol, Sch Med, Tsinghua Peking Ctr Life Sci, Beijing, Peoples R China
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关键词: Hermansky-Pudlak syndrome HPS1 large dense core vesicle Paneth cell inflammatory bowel disease VAMP7

摘要:
HPS1, a BLOC-3 subunit that acts as a guanine nucleotide exchange factor of Rab32/38, may play a role in the removal of VAMP7 during the maturation of large dense core vesicles of Paneth cells. Loss of HPS1 impairs lysozyme secretion and alters the composition of intestinal microbiota, which may explain the susceptibility of HPS-associated inflammatory bowel disease. Hermansky-Pudlak syndrome (HPS) is characterized by oculocutaneous albinism, bleeding tendency, and other chronic organ lesions due to defects in tissue-specific lysosome-related organelles (LROs). For some HPS subtypes, such as HPS-1, it is common to have symptoms of HPS-associated inflammatory bowel disease (IBD). However, its underlying mechanism is largely unknown. HPS1 is a subunit of the BLOC-3 complex which functions in the biogenesis of LROs. Large dense core vesicles (LDCVs) in Paneth cells of the intestine are a type of LROs. We here first report the abnormal LDCV morphology (increased number and enlarged size) in HPS1-deficient pale ear (ep) mice. Similar to its role in melanosome maturation, HPS1 plays an important function in the removal of VAMP7 from LDCVs to promote the maturation of LDCVs. The immature LDCVs in ep mice are defective in regulated secretion of lysozyme, a key anti-microbial peptide in the intestine. We observed changes in the composition of intestinal microbiota in both HPS-1 patients and ep mice. These findings provide insights into the underlying mechanism of HPS-associated IBD development, which may be implicated in possible therapeutic intervention of this devastating condition.

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基金编号: 2019YFA0802104 91954104 91542118 31830054 91539204 31730028 5164032

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出版当年[2019]版:
大类 | 2 区 医学
小类 | 2 区 免疫学
最新[2023]版:
大类 | 2 区 医学
小类 | 2 区 免疫学
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出版当年[2018]版:
Q2 IMMUNOLOGY
最新[2023]版:
Q1 IMMUNOLOGY

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第一作者机构: [1]Capital Med Univ, Genet & Birth Defects Control Ctr,Beijing Pediat, Beijing Childrens Hosp,MOE Key Lab Major Dis Chil, Natl Ctr Childrens Hlth,Beijing Key Lab Genet Bir, Beijing, Peoples R China [2]Univ Chinese Acad Sci, Chinese Acad Sci, Inst Genet & Dev Biol, Beijing, Peoples R China
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