{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMembers of the membrane‐associated RING-CH family, including MARCHF9 (also referred to as MARCH9), function as transmembrane E3 ubiquitin ligases that critically modulate the immune microenvironment. For instance, in glioblastoma an amplification at the CDK4–MARCH9 locus is associated with a subgroup of tumors exhibiting a diminished adaptive immune response, underscoring a role in shaping immunosuppressive conditions that may impair effective antitumoral immunity."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMARCH family proteins exert their regulatory activities by directly ubiquitinating key cell-surface molecules involved in immune recognition and cell adhesion. Early studies identified that overexpression of a MARCH family member—referred to as MARCH-IX—leads to the downregulation of major histocompatibility complex (MHC) class I molecules and the T-cell co-receptor CD4, while also controlling the surface expression of the adhesion molecule ICAM-1. Complementary findings further revealed that MARCH9, along with its closely related counterpart MARCH4, targets the NKG2D ligand Mult1 for ubiquitination, a modification that can be dynamically reversed under stress conditions such as heat shock."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn addition to regulating surface expression, MARCHF9-mediated ubiquitination plays an essential role in intracellular trafficking. Specifically, ubiquitination of MHC I by MARCH9 directs these molecules from the trans-Golgi network into endosomal compartments—a process that is critical for efficient antigen cross-presentation by immune cells. Detailed structural studies further demonstrated that particular residues within the α-helical regions of MARCH9’s transmembrane domains, including a critical serine, are indispensable for substrate recognition and the subsequent ubiquitin transfer."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond their immunomodulatory roles, MARCHF9 also appears to influence oncogenic processes. In lung adenocarcinoma, MARCH9 has been investigated for its potential impact on tumor progression, while studies in colorectal cancer have revealed that high MARCHF9 expression correlates with advanced clinical stages, metastasis, and poorer overall and disease-free survival. Functional assays further support these clinical observations by showing that downregulation of MARCHF9 in colon adenocarcinoma cell lines attenuates cell proliferation and invasion, suggesting that aberrant MARCHF9 activity contributes to tumorigenesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": "\n"}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Suvi Luoto, Ismaïl Hermelo, Elisa M Vuorinen, et al. 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