LMAN1 是血小板生成素的货物受体。

IF 6.3 1区 医学 Q1 MEDICINE, RESEARCH & EXPERIMENTAL JCI insight Pub Date : 2024-11-05 DOI:10.1172/jci.insight.175704
Lesley A Everett, Zesen Lin, Ann Friedman, Vi T Tang, Greggory Myers, Ginette Balbin-Cuesta, Richard King, Guojing Zhu, Beth McGee, Rami Khoriaty
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引用次数: 0

摘要

促血小板生成素(TPO)是一种血浆糖蛋白,能与巨核细胞(MK)和巨核细胞祖细胞上的受体结合,从而促进血小板生成。人们对 TPO 从肝细胞分泌的机制仍知之甚少。LMAN1 和 MCFD2 在内质网膜上形成复合物,将货物蛋白招募到 COPII 囊泡中进行分泌。在这项研究中,我们发现 LMAN1 缺乏的小鼠(LMAN1 基因完全缺乏)表现出轻度血小板减少,而 Lman1 表达量约为 7% 的小鼠血小板计数完全正常。令人惊讶的是,缺失 Mcfd2 的小鼠没有血小板减少症。对 LMAN1 缺失小鼠外周血的分析表明,血小板大小正常,致密颗粒和α颗粒形态正常。LMAN1 基因缺陷小鼠骨髓中的 MK 和 MK 祖细胞呈减少趋势。我们接下来的研究表明,肝细胞特异性 Lman1 基因缺失会导致血小板减少,而造血 Lman1 基因缺失不会导致血小板减少,尽管 LMAN1 基因缺失的肝脏中 Tpo mRNA 水平正常,但 LMAN1 基因缺失小鼠的血浆 TPO 水平会降低。在异源细胞系中,TPO和LMAN1通过共免疫沉淀相互作用,TPO在LMAN1缺失的细胞内积累。总之,这些研究证实肝细胞是体内产生 TPO 的起源细胞,并且 LMAN1 是介导 TPO 有效分泌的内质网货物受体。据我们所知,TPO是第一个独立于MCFD2的依赖LMAN1的货物。
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LMAN1 serves as a cargo receptor for thrombopoietin.

Thrombopoietin (TPO) is a plasma glycoprotein that binds its receptor on megakaryocytes (MK) and MK progenitors, resulting in enhanced platelet production. The mechanism by which TPO is secreted from hepatocytes remains poorly understood. LMAN1 and MCFD2 form a complex at the endoplasmic reticulum membrane, recruiting cargo proteins into COPII vesicles for secretion. In this study, we showed that LMAN1 deficient mice (with complete germline LMAN1 deficiency) exhibited mild thrombocytopenia, whereas the platelet count was entirely normal in mice with approximately 7% Lman1 expression. Surprisingly, mice deleted for Mcfd2 did not exhibit thrombocytopenia. Analysis of peripheral blood from LMAN1 deficient mice demonstrated normal platelet size and normal morphology of dense and alpha granules. LMAN1 deficient mice exhibited a trend toward reduced MK and MK progenitors in the bone marrow. We next showed that hepatocyte-specific but not hematopoietic Lman1 deletion results in thrombocytopenia, with plasma TPO level reduced in LMAN1 deficient mice, despite normal Tpo mRNA levels in LMAN1 deficient livers. TPO and LMAN1 interacted by co-immunoprecipitation in a heterologous cell line and TPO accumulated intracellularly in LMAN1 deleted cells. Altogether, these studies confirmed the hepatocyte as the cell of origin for TPO production in vivo and were consistent with LMAN1 as the endoplasmic reticulum cargo receptor that mediates the efficient secretion of TPO. To our knowledge, TPO is the first example of an LMAN1-dependent cargo that is independent of MCFD2.

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来源期刊
JCI insight
JCI insight Medicine-General Medicine
CiteScore
13.70
自引率
1.20%
发文量
543
审稿时长
6 weeks
期刊介绍: JCI Insight is a Gold Open Access journal with a 2022 Impact Factor of 8.0. It publishes high-quality studies in various biomedical specialties, such as autoimmunity, gastroenterology, immunology, metabolism, nephrology, neuroscience, oncology, pulmonology, and vascular biology. The journal focuses on clinically relevant basic and translational research that contributes to the understanding of disease biology and treatment. JCI Insight is self-published by the American Society for Clinical Investigation (ASCI), a nonprofit honor organization of physician-scientists founded in 1908, and it helps fulfill the ASCI's mission to advance medical science through the publication of clinically relevant research reports.
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