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Essential role of MFSD1-GLMP-GIMAP5 in lymphocyte survival and liver homeostasis

ABSTRACT: In this study, we detected three alleles that caused lymphopenia, splenomegaly, progressive liver pathology and extramedullary hematopoiesis (EMH), resulting from N-ethyl-N-nitrosourea (ENU)-induced mutations in the major facilitator superfamily domain containing 1 protein (Mfsd1) which encodes a lysosomal membrane-bound solute carrier protein with no previously described function in immunity. By proteomic analysis, we identified MFSD1 functions together with GLMP (glycosylated lysosomal membrane protein), and GIMAP5 (GTPase of immunity-associated protein 5). Germ line knock alleles of MFSD1, GLMP, and GIMAP5 were generated in mice and confirmed occurrence of lymphopenia, liver pathology, EMH, and lipid deposition in the bone marrow and liver of each strain. We found that the interaction of MFSD1 and GLMP with GIMAP5 is essential to maintain normal GIMAP5 expression that is critical to support lymphocyte development and liver homeostasis that suppresses EMH. These findings provide new insight into the mechanism of how MFSD1-GLMP-GIMAP5 complex functions together to regulate immunity and liver homeostasis that were previously unknown.

INSTRUMENT(S): timsTOF Pro

ORGANISM(S): Mus Musculus (ncbitaxon:10090)

SUBMITTER: Jin Huk Choi

PROVIDER: MSV000092538 | MassIVE | Thu Jul 27 10:57:00 BST 2023

REPOSITORIES: MassIVE

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Essential role of MFSD1-GLMP-GIMAP5 in lymphocyte survival and liver homeostasis

Project description:In this study, we detected three alleles that caused lymphopenia, splenomegaly, progressive liver pathology and extramedullary hematopoiesis (EMH), resulting from N-ethyl-N-nitrosourea (ENU)-induced mutations in the major facilitator superfamily domain containing 1 protein (Mfsd1) which encodes a lysosomal membrane-bound solute carrier protein with no previously described function in immunity. By proteomic analysis, we identified MFSD1 functions together with GLMP (glycosylated lysosomal membrane protein), and GIMAP5 (GTPase of immunity-associated protein 5). Germ line knock alleles of MFSD1, GLMP, and GIMAP5 were generated in mice and confirmed occurrence of lymphopenia, liver pathology, EMH, and lipid deposition in the bone marrow and liver of each strain. We found that the interaction of MFSD1 and GLMP with GIMAP5 is essential to maintain normal GIMAP5 expression that is critical to support lymphocyte development and liver homeostasis that suppresses EMH. These findings provide new insight into the mechanism of how MFSD1-GLMP-GIMAP5 complex functions together to regulate immunity and liver homeostasis that were previously unknown.

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