{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nMARCHF6 (also known as TEB4 in humans) is an endoplasmic reticulum‐resident E3 ubiquitin ligase that plays a central role in maintaining cellular homeostasis by targeting key proteins for proteasomal degradation. Early studies established that MARCHF6 controls the turnover of crucial cholesterol biosynthetic enzymes such as squalene monooxygenase (SM) and 3‐hydroxy-3‐methylglutaryl coenzyme A reductase (HMGCR), as well as influencing the ubiquitination status of SM under different metabolic conditions including unsaturated fatty acid exposure. Structural analyses comparing yeast Doa10 with its human ortholog further revealed a conserved membrane topology and a critical C-terminal element that governs substrate recognition."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "4"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its classical role in sterol regulation, MARCHF6 is implicated in broader protein quality control processes. It cooperates with other ER-resident ubiquitin ligases to manage the degradation of misfolded or damaged proteins such as the soluble mCherry-CL1 reporter and the tail-anchored heme oxygenase-1 (HO-1). MARCHF6-dependent ER-associated degradation also modulates the turnover of mutant forms of NPC1—illustrating its importance in pathological conditions like Niemann–Pick type C disease—and is tightly regulated by cholesterol levels, as cholesterol can stabilize MARCHF6 by preventing its autoubiquitination. Additional studies have identified MARCHF6 as a multifaceted regulator that orchestrates the degradation of further cholesterol synthesis enzymes including squalene epoxidase (SQLE), lanosterol 14α-demethylase (LDM), and 24-dehydrocholesterol reductase, with impacts on endothelial barrier function and angiogenesis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "11"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nRecent findings have also uncovered roles for MARCHF6 in disease pathogenesis beyond metabolic regulation. In the nervous system, intronic TTTTA/TTTCA repeat expansions in the MARCH6 gene underlie a form of Familial Adult Myoclonic Epilepsy (FAME3), while in cancers, alterations in MARCHF6 expression can influence tumor development. In prostate cancer, transcriptional upregulation of MARCHF6 by Sp1 correlates with enhanced cholesterol accretion, whereas in papillary thyroid carcinoma, increased MARCHF6 expression promotes tumorigenesis through destabilization of substrates such as DHX9 and activation of the AKT/mTOR pathway."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "12", "end_ref": "14"}]}, {"type": "t", "text": "\n"}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Stefan G Kreft, Lin Wang, Mark Hochstrasser "}, {"type": "b", "children": [{"type": "t", "text": "Membrane topology of the yeast endoplasmic reticulum-localized ubiquitin ligase Doa10 and comparison with its human ortholog TEB4 (MARCH-VI)."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2006)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M512215200"}], "href": "https://doi.org/10.1074/jbc.M512215200"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "16373356"}], "href": "https://pubmed.ncbi.nlm.nih.gov/16373356"}]}, {"type": "r", "ref": 2, "children": [{"type": "t", "text": "Noam Zelcer, Laura J Sharpe, Anke Loregger, et al. "}, {"type": "b", "children": [{"type": "t", "text": "The E3 ubiquitin ligase MARCH6 degrades squalene monooxygenase and affects 3-hydroxy-3-methyl-glutaryl coenzyme A reductase and the cholesterol synthesis pathway."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Mol Cell Biol (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1128/MCB.01140-13"}], "href": "https://doi.org/10.1128/MCB.01140-13"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24449766"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24449766"}]}, {"type": "r", "ref": 3, "children": [{"type": "t", "text": "Julian Stevenson, Winnie Luu, Ika Kristiana, et al. "}, {"type": "b", "children": [{"type": "t", "text": "Squalene mono-oxygenase, a key enzyme in cholesterol synthesis, is stabilized by unsaturated fatty acids."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "Biochem J (2014)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1042/BJ20131404"}], "href": "https://doi.org/10.1042/BJ20131404"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "24840124"}], "href": "https://pubmed.ncbi.nlm.nih.gov/24840124"}]}, {"type": "r", "ref": 4, "children": [{"type": "t", "text": "Dimitrios Zattas, Jason M Berk, Stefan G Kreft, et al. "}, {"type": "b", "children": [{"type": "t", "text": "A Conserved C-terminal Element in the Yeast Doa10 and Human MARCH6 Ubiquitin Ligases Required for Selective Substrate Degradation."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "J Biol Chem (2016)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.1074/jbc.M116.726877"}], "href": "https://doi.org/10.1074/jbc.M116.726877"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "27068744"}], "href": "https://pubmed.ncbi.nlm.nih.gov/27068744"}]}, {"type": "r", "ref": 5, "children": [{"type": "t", "text": "Sandra Stefanovic-Barrett, Anna S Dickson, Stephen P Burr, et al. "}, {"type": "b", "children": [{"type": "t", "text": "MARCH6 and TRC8 facilitate the quality control of cytosolic and tail-anchored proteins."}]}, {"type": "t", "text": " "}, {"type": "i", "children": [{"type": "t", "text": "EMBO Rep (2018)"}]}, {"type": "t", "text": " DOI: "}, {"type": "a", "children": [{"type": "t", "text": "10.15252/embr.201745603"}], "href": "https://doi.org/10.15252/embr.201745603"}, {"type": "t", "text": " PMID: "}, {"type": "a", "children": [{"type": "t", "text": "29519897"}], "href": "https://pubmed.ncbi.nlm.nih.gov/29519897"}]}, {"type": "r", "ref": 6, "children": [{"type": "t", "text": "Mark L Schultz, Kelsey L Krus, Susmita Kaushik, et al. 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