{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMARCHF2 (also known as MARCH2 or MARCH-II) functions as a key regulator of intracellular membrane trafficking. It localizes to endosomal vesicles and the plasma membrane, where it interacts with proteins such as syntaxin 6 to modulate trafficking between the trans-Golgi network (TGN) and endosomes, leading to altered recycling and cell surface expression of receptors like transferrin receptor. In addition, MARCHF2 associates with PDZ domain–containing scaffolds—for example, interacting with DLG1 at cell–cell junctions—and it ubiquitinates cargo receptors such as ERGIC3, thereby influencing the early secretory pathway and secretion of proteins including α1-antitrypsin and haptoglobin."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nMARCHF2 also governs receptor fate by mediating ligand-induced ubiquitination that directs substrates toward lysosomal degradation. For instance, in the presence of carvedilol, MARCHF2 binds carvedilol‐engaged β₂-adrenergic receptors, thereby promoting their ubiquitination, endocytosis, and lysosomal sorting. Similarly, by interacting with the CAL complex (involving CFTR-associated ligand and syntaxin 6), MARCHF2 targets mature CFTR for lysosomal degradation. In its antiviral roles, MARCHF2 reduces the incorporation of viral envelope glycoproteins into budding virions—thereby impairing viral entry—and is upregulated in response to viral infection such as HIV-1, contributing to suppression of viral production. Additionally, MARCHF2 restricts Ebola virus glycoprotein maturation through similar mechanisms."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "8"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond these roles, MARCHF2 influences cellular processes that contribute to cancer biology. It acts as a negative regulator of autophagy by promoting the ubiquitination and degradation of CFTR, thereby impacting CFTR-mediated autophagic flux. Moreover, MARCHF2 has been identified as a novel SNAIL E3 ligase; by targeting SNAIL for degradation, it modulates epithelial–mesenchymal transition (EMT) and suppresses tumor metastasis, particularly in triple-negative breast cancer. Its ability to selectively downregulate VE-cadherin further underscores its role in modulating cell–cell adhesion and vascular integrity. Emerging evidence also suggests that MARCHF2 is implicated in inflammatory responses and protein trafficking in hepatocellular carcinoma."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "9", "end_ref": "12"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Nobuhiro Nakamura, Hidekazu Fukuda, Akira Kato, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MARCH-II is a syntaxin-6-binding protein involved in endosomal trafficking."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Biol Cell (2005)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1091/mbc.e04-03-0216"}], "href": "https://doi.org/10.1091/mbc.e04-03-0216"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "15689499"}], "href": "https://pubmed.ncbi.nlm.nih.gov/15689499"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Zhifang Cao, Alan Huett, Petric Kuballa, et al. "}, {"type": "b", "children": [{"type": "t", "text": "DLG1 is an anchor for the E3 ligase MARCH2 at sites of cell-cell contact."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cell Signal (2008)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.cellsig.2007.08.019"}], "href": "https://doi.org/10.1016/j.cellsig.2007.08.019"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "17980554"}], "href": "https://pubmed.ncbi.nlm.nih.gov/17980554"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Wonjin Yoo, Eun-Bee Cho, Sungjoo Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The E3 ubiquitin ligase MARCH2 regulates ERGIC3-dependent trafficking of secretory proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.RA119.007435"}], "href": "https://doi.org/10.1074/jbc.RA119.007435"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "31142615"}], "href": "https://pubmed.ncbi.nlm.nih.gov/31142615"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Sang-oh Han, Kunhong Xiao, Jihee Kim, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MARCH2 promotes endocytosis and lysosomal sorting of carvedilol-bound β(2)-adrenergic receptors."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Cell Biol (2012)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1083/jcb.201208192"}], "href": "https://doi.org/10.1083/jcb.201208192"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23166351"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23166351"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Jie Cheng, William Guggino "}, {"type": "b", "children": [{"type": "t", "text": "Ubiquitination and degradation of CFTR by the E3 ubiquitin ligase MARCH2 through its association with adaptor proteins CAL and STX6."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2013)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0068001"}], "href": "https://doi.org/10.1371/journal.pone.0068001"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "23818989"}], "href": "https://pubmed.ncbi.nlm.nih.gov/23818989"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Yanzhao Zhang, Takuya Tada, Seiya Ozono, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Membrane-associated RING-CH (MARCH) 1 and 2 are MARCH family members that inhibit HIV-1 infection."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2019)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.AC118.005907"}], "href": "https://doi.org/10.1074/jbc.AC118.005907"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "30630952"}], "href": "https://pubmed.ncbi.nlm.nih.gov/30630952"}]}, {"type": "r", "ref": 7, "children": [{"type": "t", "text": "You Zhang, Jing Lu, Xinqi Liu "}, {"type": "b", "children": [{"type": "t", "text": "MARCH2 is upregulated in HIV-1 infection and inhibits HIV-1 production through envelope protein translocation or degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Virology (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.virol.2018.02.003"}], "href": "https://doi.org/10.1016/j.virol.2018.02.003"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29573664"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29573664"}]}, {"type": "r", "ref": 8, "children": [{"type": "t", "text": "Changqing Yu, Yuanzhe Bai, Wenbo Tan, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Human MARCH1, 2, and 8 block Ebola virus envelope glycoprotein cleavage via targeting furin P domain."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Med Virol (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1002/jmv.29445"}], "href": "https://doi.org/10.1002/jmv.29445"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38299743"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38299743"}]}, {"type": "r", "ref": 9, "children": [{"type": "t", "text": "Dan Xia, Liujing Qu, Ge Li, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MARCH2 regulates autophagy by promoting CFTR ubiquitination and degradation and PIK3CA-AKT-MTOR signaling."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Autophagy (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1080/15548627.2016.1192752"}], "href": "https://doi.org/10.1080/15548627.2016.1192752"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27308891"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27308891"}]}, {"type": "r", "ref": 10, "children": [{"type": "t", "text": "Koichi Ito, Ibuki Harada, Criseyda Martinez, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MARCH2, a Novel Oncogene-regulated SNAIL E3 Ligase, Suppresses Triple-negative Breast Cancer Metastases."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Cancer Res Commun (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1158/2767-9764.CRC-23-0090"}], "href": "https://doi.org/10.1158/2767-9764.CRC-23-0090"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38457262"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38457262"}]}, {"type": "r", "ref": 11, "children": [{"type": "t", "text": "Tadahiko Seo, Anthony M Lowery, Haifang Xu, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MARCH family E3 ubiquitin ligases selectively target and degrade cadherin family proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "PLoS One (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1371/journal.pone.0290485"}], "href": "https://doi.org/10.1371/journal.pone.0290485"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38722959"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38722959"}]}, {"type": "r", "ref": 12, "children": [{"type": "t", "text": "Dongsheng Ni, Zhaolai Qi, Yuefeng Wang, et al. "}, {"type": "b", "children": [{"type": "t", "text": "KLF15-activated MARCH2 boosts cell proliferation and epithelial-mesenchymal transition and presents diagnostic significance for hepatocellular carcinoma."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Exp Cell Res (2024)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1016/j.yexcr.2024.114117"}], "href": "https://doi.org/10.1016/j.yexcr.2024.114117"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "38848952"}], "href": "https://pubmed.ncbi.nlm.nih.gov/38848952"}]}]}]}