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The mechanism by which TPO is secreted from hepatocytes remains poorly understood. Lectin mannose-binding 1 (LMAN1) and multiple coagulation factor deficiency 2 (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%\n                    <jats:italic>Lman1<\/jats:italic>\n                    expression. Surprisingly, mice deleted for\n                    <jats:italic>Mcfd2<\/jats:italic>\n                    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\n                    <jats:italic>Lman1<\/jats:italic>\n                    deletion results in thrombocytopenia, with plasma TPO level reduced in LMAN1-deficient mice, despite normal\n                    <jats:italic>Tpo<\/jats:italic>\n                    mRNA levels in LMAN1-deficient livers. TPO and LMAN1 interacted by coimmunoprecipitation in a heterologous cell line, and TPO accumulated intracellularly in\n                    <jats:italic>LMAN1<\/jats:italic>\n                    -deleted cells. Together, these studies verified 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.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.175704","type":"journal-article","created":{"date-parts":[[2024,11,5]],"date-time":"2024-11-05T12:00:19Z","timestamp":1730808019000},"source":"Crossref","is-referenced-by-count":1,"title":["LMAN1 serves as a cargo receptor for thrombopoietin"],"prefix":"10.1172","volume":"9","author":[{"given":"Lesley A.","family":"Everett","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and"},{"name":"Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA."}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Zesen","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Pharmacology,"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ann","family":"Friedman","sequence":"additional","affiliation":[{"name":"Department of 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