Affinage

MARCHF6

E3 ubiquitin-protein ligase MARCHF6 · UniProt O60337

Length
910 aa
Mass
102.5 kDa
Annotated
2026-06-10
37 papers in source corpus 26 papers cited in narrative 26 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 8/8 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MARCHF6 (TEB4/MARCH6) is a multi-pass ER-resident RING-CH E3 ubiquitin ligase that orchestrates protein quality control and lipid homeostasis by targeting membrane and cytosolic substrates for proteasomal degradation (PMID:15673284, PMID:23898401). Its N-terminal C4HC3 RING domain faces the cytosol and catalyzes Lys48-linked ubiquitination in vitro using UBC7/UBE2J2 as the cognate E2, and the enzyme constitutively autoubiquitinates to drive its own turnover (PMID:15673284, PMID:16373356). Cryo-EM revealed that the protein folds into a unique circular, lipid-binding scaffold gated by a flexible helical bundle, with the RING active site positioned over the channel; substrate degradation depends on this gated channel and on RING-domain connections to the membrane scaffold (PMID:38195637). A dominant function is feedback control of cholesterol synthesis: MARCHF6 degrades multiple sequential mevalonate-pathway enzymes including squalene monooxygenase, HMGCR, lanosterol 14α-demethylase, DHCR24, and SC4MOL, and acts as an endogenous brake on the SREBP program by ubiquitinating SREBP1 (PMID:23898401, PMID:24449766, PMID:31904814, PMID:36958722, PMID:42173365). Substrate recognition occurs through distinct cytosol-facing determinants, including an Ac/N-degron domain that preferentially binds Nα-terminally acetylated substrates such as RGS2 and PLIN2, and a conserved C-terminal element (CTE) required for a subset of substrates and for MARCHF6 autoregulation (PMID:27068744, PMID:39216628). The ligase additionally degrades pro-ferroptotic effectors ACSL4 and p53, and its activity is allosterically upregulated by NADPH binding to its C-terminal region, linking it to suppression of ferroptosis in vivo (PMID:35941365). MARCHF6 abundance is itself tightly regulated—stabilized by cholesterol (which blocks autodegradation) and by the deubiquitinase USP19, and transcriptionally driven by Sp1 (PMID:30545937, PMID:25088257, PMID:31422115). Through these activities MARCHF6 governs endothelial barrier integrity, hepatic lipogenesis, energy balance via POMC neurons, and ERAD versus ER-phagy substrate routing (PMID:32755570, PMID:42173365, PMID:37421621, PMID:30202070, PMID:41661358).

Mechanistic history

Synthesis pass · year-by-year structured walk · 24 steps
  1. 2005 High

    Establishing that human TEB4 is a bona fide E3 ligase defined the molecular activity at the heart of the gene and its E2 partner and linkage specificity.

    Evidence In vitro ubiquitin ligation with isolated RING domain, RING mutant controls, and topology/fractionation analysis

    PMID:15673284

    Open questions at the time
    • Substrate repertoire unknown at this stage
    • Full-length enzymatic activity in membrane context not addressed
  2. 2005 High

    Topology mapping of the Doa10 ortholog answered how the ligase is arranged in the ER membrane, placing both RING and C-terminus in the cytosol where they can engage E2 and substrates.

    Evidence Dual-topology reporter fusions and protease protection in yeast microsomes with comparison to human TEB4

    PMID:16373356

    Open questions at the time
    • Mechanism of substrate extraction across the membrane not defined
    • No high-resolution structure
  3. 2009 High

    Identification of type 2 deiodinase as a substrate provided the first defined endogenous target, showing the ligase controls hormone-activating enzyme levels.

    Evidence Reciprocal Co-IP and siRNA knockdown with ubiquitination, activity, and half-life readouts in two cell lines

    PMID:19651899

    Open questions at the time
    • Recognition determinant on D2 only coarsely mapped to an instability domain
    • Physiological setting of D2 regulation by TEB4 not tested in vivo
  4. 2013 High

    Demonstrating sterol-dependent degradation of squalene monooxygenase established MARCHF6 as an evolutionarily conserved node of cholesterol feedback regulation.

    Evidence Yeast genetic epistasis with mammalian Teb4 complementation and lipidomics

    PMID:23898401

    Open questions at the time
    • Direct E3-substrate engagement in mammalian cells shown subsequently
    • Sterol sensor identity unresolved
  5. 2014 High

    Direct demonstration that MARCH6 binds and degrades SM and also affects HMGCR positioned it as a regulator of multiple mevalonate-pathway enzymes.

    Evidence Reciprocal Co-IP, RING-mutant controls, knockdown with SM activity and HMGCR readouts

    PMID:24449766

    Open questions at the time
    • Whether HMGCR is a direct MARCH6 substrate or indirect not resolved here
  6. 2014 Medium

    Discovery that USP19 deubiquitinates and stabilizes MARCH6 revealed how the ligase's own abundance is post-translationally tuned against p97-driven turnover.

    Evidence Co-IP plus USP19 gain/loss of function with MARCH6 ubiquitination, stability, and p97 dependence readouts

    PMID:25088257

    Open questions at the time
    • Single lab
    • Stoichiometry and regulation of the USP19-MARCH6 interaction unknown
  7. 2015 Medium

    Showing MARCH6 loss induces IDOL and LDLR degradation explained how the ligase uncouples cholesterol synthesis from lipoprotein uptake at the systems level.

    Evidence MARCH6 knockdown/knockout with gene expression, uptake assays, and IDOL epistasis

    PMID:26527619

    Open questions at the time
    • Mechanism linking MARCH6 loss to IDOL induction not defined
    • Single lab
  8. 2016 Medium

    Mapping the conserved C-terminal element defined a substrate-recognition/autoregulation determinant distinct from the RING and confirmed endogenous ER localization.

    Evidence CTE mutagenesis (N890A) with yeast and human degradation assays plus CRISPR endogenous tagging

    PMID:27068744

    Open questions at the time
    • Structural basis of CTE function unresolved at this stage
    • Which substrates require CTE not exhaustively mapped
  9. 2018 High

    Cooperation of MARCH6 with TRC8 and the protease SPP showed the ligase participates in degrading misfolded and intramembrane-cleaved substrates such as HO-1.

    Evidence Forward genetic screens, CRISPR double knockout, SPP Co-IP, and quantitative MS

    PMID:29519897

    Open questions at the time
    • Division of labor between MARCH6 and TRC8 per substrate not fully delineated
  10. 2018 Medium

    Demonstrating cholesterol stabilizes MARCH6 by blocking autodegradation established a direct feedback loop coupling sterol levels to ligase abundance and substrate flux.

    Evidence CRISPR editing, autodegradation mutants, and VCP/p97 and proteasome inhibition

    PMID:30545937

    Open questions at the time
    • Sterol-sensing domain ruled out but the actual sensing mechanism unidentified
    • Single lab
  11. 2018 Medium

    Identifying MARCH6-dependent degradation of misfolded NPC1 positioned the ligase within ERAD acting in parallel to FAM134B-mediated ER-phagy.

    Evidence siRNA knockdown with proteasomal readouts and in vivo mouse tissue analysis

    PMID:30202070

    Open questions at the time
    • Direct interaction of MARCH6 with NPC1 not shown
    • Single lab
  12. 2019 Medium

    Sp1 was identified as a transcriptional activator of MARCH6, defining how ligase levels are set at the gene-expression layer with downstream effects on SM stability.

    Evidence Luciferase reporters, promoter deletion, Sp1 inhibition/knockdown, and ChIP-seq mining

    PMID:31422115

    Open questions at the time
    • Whether Sp1 regulation responds to metabolic cues not addressed
    • Single lab
  13. 2020 Medium

    Establishing LDM and DHCR24 as substrates, in a sterol-independent manner, showed MARCH6 controls multiple cholesterol-synthesis steps beyond SM.

    Evidence siRNA knockdown with substrate stability and sterol-manipulation controls

    PMID:31904814

    Open questions at the time
    • Direct ubiquitination of these substrates not shown
    • Recognition determinants undefined
  14. 2020 Medium

    Linking MARCH6-mediated SQLE degradation to endothelial membrane order and barrier function extended the ligase's lipid role to tissue physiology.

    Evidence MARCHF6 ablation and SQLE overexpression with membrane-order, barrier, and angiogenesis assays

    PMID:32755570

    Open questions at the time
    • In vivo vascular phenotype not tested
    • Single lab
  15. 2021 Medium

    Degradation of DHX9 connected MARCH6 to AKT/mTOR signaling and proliferation in thyroid cancer, broadening substrates beyond lipid metabolism.

    Evidence Co-IP, MARCH6 overexpression/knockdown, DHX9 knockdown epistasis, and pathway/phenotype readouts

    PMID:34512155

    Open questions at the time
    • Direct ubiquitination of DHX9 not rigorously shown
    • Single lab/cancer context
  16. 2022 High

    Discovery that NADPH binds and activates MARCHF6 and that the ligase degrades ACSL4 and p53 revealed an allosteric metabolic sensor controlling ferroptosis suppression.

    Evidence NADPH binding and ligase-activity assays, ubiquitination of ACSL4/p53, and knockout mice with ferroptosis-rescue

    PMID:35941365

    Open questions at the time
    • Structural basis of NADPH binding/activation not resolved
    • Relative contribution of each substrate to ferroptosis phenotype unclear
  17. 2023 Medium

    Identification of SC4MOL as a substrate brought the count of MARCH6-controlled cholesterol-synthesis enzymes to at least five, cementing it as a multi-enzyme pathway regulator.

    Evidence siRNA knockdown with substrate stability and sterol-manipulation controls in two cell systems

    PMID:36958722

    Open questions at the time
    • Direct ubiquitination of SC4MOL not shown
    • Single lab
  18. 2023 Medium

    Degradation of cytosol-retained POMC by Marchf6 in hypothalamic neurons tied the ligase to ER-stress/ferroptosis protection and systemic energy balance.

    Evidence POMC-Cre conditional knockout mice with ER-stress, ferroptosis, and metabolic phenotyping

    PMID:37421621

    Open questions at the time
    • Generalizability to other mislocalized substrates unknown
    • Single lab
  19. 2023 Medium

    The Brucella effector BspA was shown to destabilize MARCH6 and inhibit ERAD, identifying the ligase as a target hijacked during bacterial infection.

    Evidence Co-IP, MARCH6 siRNA, pharmacological ERAD inhibition, and bacterial replication assays in macrophages

    PMID:37129527

    Open questions at the time
    • Mechanism by which BspA destabilizes the complex not detailed
    • Single lab
  20. 2024 High

    Cryo-EM solved the unique circular channel architecture and, with 95-variant mutagenesis, defined how the gated channel, RING connections, and lipid-binding sites drive substrate degradation.

    Evidence Cryo-EM, AlphaFold modeling, systematic mutagenesis, and SQLE degradation assays

    PMID:38195637

    Open questions at the time
    • Substrate-engaged and ubiquitylation-complex states only modeled, not directly resolved
    • Mechanism of membrane substrate retrotranslocation not visualized
  21. 2024 High

    Mapping the Ac/N-degron recognition domain explained how MARCHF6 selectively binds Nα-terminally acetylated substrates like RGS2 and PLIN2, defining a discrete degron-reading module.

    Evidence Alanine-stretch mutagenesis, crosslinking Co-IP, split-ubiquitin assays, and acetylated vs unacetylated binding assays

    PMID:39216628

    Open questions at the time
    • Structural view of the Ac/N domain bound to degron not available
    • Full set of Ac/N-degron substrates undefined
  22. 2025 Medium

    An E3-activity-independent role degrading Tembusu virus NS5 via TOLLIP-mediated selective autophagy revealed a non-canonical, ubiquitin-independent function for MARCH6 as an autophagic adaptor.

    Evidence Co-IP, RING-dead mutant, autophagy inhibitors, and viral replication assays in avian system

    PMID:40511919

    Open questions at the time
    • Generalization to mammalian MARCHF6 untested
    • How a ligase scaffolds autophagy receptors mechanistically unclear
  23. 2026 Medium

    Direct ubiquitination of SREBP1 and the hepatic-knockout lipogenesis phenotype established MARCHF6 as a proteostatic brake on de novo lipogenesis relevant to fatty liver disease.

    Evidence Liver-specific knockout mice, Co-IP, ubiquitination and half-life assays, multi-omics, and human MASLD data

    PMID:42173365

    Open questions at the time
    • Recognition determinant on SREBP1 undefined
    • Single lab
  24. 2026 Medium

    Ubiquitination-driven degradation of FAM134B in glioma showed MARCH6 actively suppresses ER-phagy, complementing its ERAD role in setting ER homeostasis balance.

    Evidence Co-IP, ubiquitination assays, knockdown epistasis, ER-stress/autophagy markers, and mouse glioma model

    PMID:41661358

    Open questions at the time
    • Recognition of FAM134B not mapped
    • Single lab

Open questions

Synthesis pass · forward-looking unresolved questions
  • How lipid composition, NADPH, cholesterol, and degron type are integrated by the channel architecture to select among the diverse substrate repertoire, and the structural basis of substrate retrotranslocation, remain unresolved.
  • No substrate-bound structure
  • Rules governing substrate selection across degron classes undefined
  • In vivo hierarchy among substrates and tissues unclear

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 4 GO:0008289 lipid binding 2 GO:0016874 ligase activity 2 GO:0060090 molecular adaptor activity 2 GO:0140299 molecular sensor activity 2
Localization
GO:0005783 endoplasmic reticulum 3
Pathway
R-HSA-1430728 Metabolism 5 R-HSA-392499 Metabolism of proteins 3 R-HSA-5357801 Programmed Cell Death 3 R-HSA-9612973 Autophagy 3
Partners
DHX9FAM134BSPPSQLESREBP1TRC8UBE2J2USP19

Evidence

Reading pass · 26 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2005 Human TEB4 (MARCHF6) is an ER-resident ubiquitin ligase with a C4HC3 RING finger at its N-terminus located in the cytosol. The isolated RING domain catalyzes ubiquitin ligation in vitro in a Lys48-specific manner involving UBC7 as the E2. TEB4 promotes its own proteasomal degradation in a RING finger-dependent manner (autoubiquitination). In vitro ubiquitin ligation assay with isolated RING domain; mutational analysis of RING finger; proteasomal inhibitor experiments; subcellular fractionation/topology analysis The Biochemical journal High 15673284
2005 Yeast Doa10 (ortholog of human TEB4/MARCHF6) contains 14 transmembrane helices with both its N-terminal RING-CH domain and C-terminus facing the cytosol. Biochemical evidence supports a similar topology for human TEB4 (MARCHF6). The yeast Derlins are not required for degradation of Doa10 membrane substrates. Dual-topology reporter fusions at 16 positions in Doa10; protease digestion of yeast microsomes; bioinformatic topology prediction; in silico mutagenesis; topology comparison with human TEB4 The Journal of biological chemistry High 16373356
2009 TEB4 (MARCHF6) interacts with and mediates ubiquitination and degradation of type 2 iodothyronine deiodinase (D2). TEB4 knockdown decreases D2 ubiquitination and increases D2 activity and protein levels ~4-fold, prolonging D2 half-life. The effect is specific to D2 and requires a critical instability domain in D2; the other deiodinase D1 and a truncated D2 lacking the instability domain are unaffected. Co-immunoprecipitation; TEB4 overexpression (activity assay); siRNA knockdown of TEB4 (>90% reduction); measurement of D2 activity, ubiquitination, and protein levels; lentivirus-based knockdown in D2-expressing MSTO-211 cells Molecular and cellular biology High 19651899
2013 The yeast Doa10 (and its mammalian ortholog Teb4/MARCHF6) mediates sterol-dependent ubiquitination and degradation of squalene monooxygenase (SM), a sterol-specific step in the mevalonate pathway. This constitutes an evolutionarily conserved feedback system for sterol homeostasis, distinct from and complementary to HMGR (Hrd1 branch) regulation. Genetic epistasis in yeast (doa10 deletion); sterol-dependent degradation assays; lipidomics; complementation with mammalian Teb4 eLife High 23898401
2014 MARCH6 (TEB4) physically interacts with squalene monooxygenase (SM) and acts as the E3 ligase controlling its cholesterol-dependent proteasomal degradation. MARCH6 overexpression reduces SM abundance in a RING-dependent manner; MARCH6 knockdown increases SM protein and activity and prevents its cholesterol-regulated degradation. MARCH6 knockdown also increases HMGCR levels in hepatocytes, establishing MARCH6 as a regulator of both SM and HMGCR. Co-immunoprecipitation; MARCH6 overexpression with RING mutant control; siRNA knockdown; immunoblotting; SM activity assay Molecular and cellular biology High 24449766
2014 USP19, an ER-anchored deubiquitinating enzyme, interacts with MARCH6 and stabilizes it by deubiquitination, protecting MARCH6 from p97-dependent proteasomal degradation. USP19 overexpression delays MARCH6 degradation and reduces its ubiquitination; USP19 knockdown decreases MARCH6 levels and increases ubiquitination of MARCH6. Loss of USP19 also increases levels of the ERAD substrate ABCB11, consistent with MARCH6 being the mediating ligase. Co-immunoprecipitation; USP19 overexpression and siRNA knockdown; immunoblotting for MARCH6 ubiquitination and stability; p97 inhibition experiments Experimental cell research Medium 25088257
2015 MARCH6 acts as an endogenous inhibitor of the SREBP transcriptional program. Loss of MARCH6 increases SREBP-regulated gene expression (cholesterol biosynthesis and lipoprotein uptake genes) but paradoxically decreases cellular lipoprotein uptake due to enhanced lysosomal LDLR degradation. This is mediated by MARCH6-loss-induced upregulation of the E3 ligase IDOL, which drives LDLR degradation. Thus, MARCH6 uncouples cholesterol synthesis from lipoprotein uptake. Genetic knockdown/knockout of MARCH6; gene expression analysis; lipoprotein uptake assays; IDOL knockdown epistasis experiments Molecular and cellular biology Medium 26527619
2016 A conserved C-terminal element (CTE), a 16-residue cytosol-facing motif after the final TM helix of Doa10/MARCH6, is required for degradation of a subset of substrates. Mutation of the conserved asparagine in the MARCH6 CTE (N890A) stabilizes MARCH6 itself to the same degree as a catalytically inactivating RING mutation (C9A), indicating the CTE is required for MARCH6 autoregulation. CRISPR/Cas9 endogenous tagging confirmed MARCH6 localizes to the ER. Alanine/asparagine mutagenesis of CTE; yeast ubiquitylation and degradation assays; MARCH6 autoregulation assays in human cells; CRISPR/Cas9 endogenous epitope tagging for ER localization The Journal of biological chemistry Medium 27068744
2018 MARCH6 and TRC8 are both required for proteasomal degradation of misfolded cytosolic/ER-membrane substrates (mCherry-CL1 reporter); complete stabilization requires double knockout of both E3 ligases. MARCH6 and TRC8 both associate with the intramembrane protease SPP and cooperate to degrade tail-anchored heme oxygenase-1 (HO-1) following intramembrane proteolysis. The two ligases act independently of each other on these substrates. Forward genetic screens in human cells; CRISPR double knockout; quantitative mass spectrometry for protein turnover; Co-immunoprecipitation of SPP association; HO-1 degradation assays EMBO reports High 29519897
2018 Cholesterol stabilizes MARCH6 protein by preventing its autodegradation, likely through a conformational change. This stabilization requires functional VCP/p97-dependent membrane extraction and proteasomal degradation, is absent in MARCH6 autodegradation-deficient mutants, and leads to increased degradation of at least three known MARCH6 substrates (SM and others). A putative sterol-sensing domain in MARCH6 is not required for this cholesterol-mediated stabilization. CRISPR/Cas9 gene editing; MARCH6 overexpression; immunoblotting; VCP/p97 inhibition; proteasome inhibition; MARCH6 autodegradation mutants; chemical chaperone treatment The Journal of biological chemistry Medium 30545937
2018 MARCH6-dependent ERAD mediates proteasomal degradation of misfolded I1061T NPC1. This pathway acts complementarily with FAM134B-dependent selective ER autophagy (ER-phagy) to regulate I1061T NPC1 turnover. siRNA knockdown of MARCH6; proteasome inhibitor treatment; subcellular fractionation; in vivo mouse tissue analysis; identification of FAM134B-dependent ER-phagy pathway as parallel route Nature communications Medium 30202070
2019 The transcription factor Sp1 binds to three Sp1 binding sites located ~100 bp downstream of the MARCH6 transcriptional start site and upregulates MARCH6 gene expression. Pharmacological and genetic inhibition of Sp1 reduces MARCH6 expression, which in turn affects stability of its substrate squalene monooxygenase. Luciferase reporter assays; qRT-PCR; pharmacological Sp1 inhibition; siRNA knockdown of Sp1; ChIP-seq data mining; promoter deletion analysis Biochimica et biophysica acta. Molecular and cell biology of lipids Medium 31422115
2020 MARCH6 controls levels of lanosterol 14α-demethylase (LDM) and 24-dehydrocholesterol reductase (DHCR24) by promoting their degradation; this degradation is not triggered by sterols. MARCH6 thereby targets multiple steps in the cholesterol synthesis pathway, representing the first E3 ligase known to control multiple enzymes in a single biochemical pathway. siRNA knockdown of MARCH6; immunoblotting for LDM and DHCR24 stability; sterol manipulation experiments; cell-based degradation assays The Biochemical journal Medium 31904814
2020 Ablation of MARCHF6 in endothelial cells increases SQLE protein and cholesterol load, leading to altered membrane order, disorganized VE-cadherin-based adherens junctions, decreased endothelial barrier function, and impaired SQLE-dependent sprouting angiogenesis. This positions MARCH6-mediated SQLE degradation as a determinant of endothelial integrity. siRNA/CRISPR-mediated MARCHF6 ablation in endothelial cells; SQLE overexpression; cholesterol measurement; membrane order assays; barrier function assays; sprouting angiogenesis assays Cell reports Medium 32755570
2021 MARCH6 interacts with and promotes degradation (destabilization) of DHX9 in thyroid cancer cells. Mechanistically, MARCH6-mediated DHX9 destabilization activates the AKT/mTOR signaling pathway. DHX9 knockdown phenocopies MARCH6 overexpression in promoting proliferation and migration. Co-immunoprecipitation; MARCH6 overexpression and knockdown; DHX9 knockdown; AKT/mTOR pathway immunoblotting; cell proliferation and migration assays International journal of biological sciences Medium 34512155
2022 MARCHF6 recognizes NADPH through its C-terminal regulatory region; this NADPH binding upregulates MARCHF6 E3 ligase activity. MARCHF6 mediates ubiquitin-dependent degradation of the pro-ferroptotic effectors ACSL4 and p53. Loss of MARCHF6 increases ferroptosis sensitivity; inhibiting ferroptosis rescues growth of MARCHF6-deficient tumors and perinatal lethality of Marchf6-/- mice. NADPH binding assays; MARCHF6 ligase activity assays; ubiquitination assays for ACSL4 and p53; MARCHF6 knockout mice; tumor growth rescue experiments; ferroptosis inhibitor treatment Nature cell biology High 35941365
2023 SC4MOL (the first acting enzyme of the C4-demethylation complex in cholesterol synthesis) is a substrate of MARCHF6; SC4MOL is rapidly turned over and sensitive to sterols. MARCHF6 thereby controls at least five enzymes in the cholesterol synthesis pathway. siRNA knockdown of MARCHF6; sterol depletion/loading experiments; immunoblotting for SC4MOL stability; CHO and human cell lines; cholesterol measurement after SC4MOL siRNA Journal of lipid research Medium 36958722
2023 In POMC neurons, Marchf6 mediates degradation of cytosol-retained (signal peptide-uncleaved) POMC, preventing ER stress and ferroptosis. Loss of MARCHF6 in POMC neurons (POMC-Cre Marchf6-deficient mice) causes hyperphagia, reduced energy expenditure, and weight gain. POMC-Cre conditional Marchf6 knockout mice; ferroptosis and ER stress marker analysis; cell viability assays; chaperone sequestration experiments; ubiquitination assays Cell reports Medium 37421621
2023 Brucella abortus T4SS effector BspA interacts with MARCH6 and destabilizes the MARCH6 E3 ligase complex, thereby inhibiting MARCH6-dependent ERAD. This inhibition promotes intracellular B. abortus proliferation; pharmacological ERAD inhibition or siRNA depletion of MARCH6 phenocopy BspA deletion and rescue the replication defect of a bspA mutant. Co-immunoprecipitation of BspA-MARCH6; siRNA knockdown of MARCH6; pharmacological ERAD inhibition; bacterial replication assays in macrophages; epistasis with UbxD8 depletion Infection and immunity Medium 37129527
2024 Doa10/MARCHF6 adopts a unique circular architecture within the ER membrane, with the majority of the protein forming a lipid-binding scaffold gated by a flexible helical bundle. The RING domain ubiquitylation active site is positioned over this channel via connections with the membrane-spanning scaffold and gate. Structure-based mutagenesis of 95 MARCH6 variants revealed that SQLE degradation depends on the gated channel, RING domain connections, and lipid-binding sites. AlphaFold models are consistent with substrate-engaged and ubiquitylation complex states. Cryo-EM structural analysis; AlphaFold modeling; systematic mutagenesis of 95 variants; SQLE degradation assay; lipid-binding analysis Nature communications High 38195637
2024 The Ac/N-degron recognition domain (Ac/N domain) of MARCHF6 was mapped to specific cytosol-facing regions using alanine-stretch mutagenesis. This domain exhibits preferential binding to Nα-terminally acetylated proteins/peptides over unacetylated counterparts. MARCHF6 mediates degradation of Ac/N-degron-bearing substrates including RGS2 and PLIN2, and abolishing Ac/N-degron recognition stabilizes these substrates and increases ferroptosis resistance. Alanine-stretch mutagenesis; chemical crosslinking-based Co-IP; split-ubiquitin assays (human and yeast cells); Ac/N-degron substrate binding assays with acetylated vs. unacetylated peptides; RGS2 and PLIN2 stability assays; ferroptosis assays The Journal of biological chemistry High 39216628
2025 Avian MARCH6 directly interacts with Tembusu virus NS5 protein and promotes its degradation via selective autophagy through an E3 ligase activity-independent mechanism. MARCH6 recruits the autophagic cargo receptor TOLLIP, which facilitates NS5-TOLLIP interaction independent of ubiquitin signaling, directing NS5 to phagophores for degradation. Co-immunoprecipitation of MARCH6-NS5 and NS5-TOLLIP; MARCH6 overexpression and knockdown; RING-dead MARCH6 mutant; autophagy inhibitors; viral replication assays Journal of virology Medium 40511919
2026 MARCHF6 directly interacts with and ubiquitinates SREBP1, targeting it for proteasomal degradation. Loss of hepatic MARCHF6 prolongs SREBP1 half-life, driving excessive de novo lipogenesis. Liver-specific Marchf6 knockout mice develop spontaneous hepatic triglyceride and cholesteryl ester accumulation under normal chow. Liver-specific Marchf6 knockout (Marchf6Alb) mice; Co-IP; ubiquitination assay; SREBP1 half-life measurement; transcriptomics and proteomics; lipidomics; human MASLD patient data Journal of hepatology Medium 42173365
2026 MARCH6 induces FAM134B protein ubiquitination and degradation, reducing FAM134B stability in glioma cells. This suppresses ER-phagy and ER stress responses. Knockdown of MARCH6 reverses FAM134B degradation and restores ER-phagy markers (LC3B conversion, autophagosome accumulation). Co-immunoprecipitation (MARCH6-FAM134B interaction); ubiquitination assays; siRNA knockdown of FAM134B and MARCH6; ER stress and autophagy marker analysis; mouse glioma model Neurochemical research Medium 41661358
2025 The membrane-anchored E2 UBE2J2 cooperates with MARCHF6 (and other E3 ligases RNF145, RNF139) to ubiquitinate both themselves and the substrate squalene monooxygenase. UBE2J2 activity is modulated by membrane lipid packing, with loosely packed membranes impairing ubiquitin loading onto UBE2J2, thereby relaying lipid signals to MARCHF6-dependent ubiquitination. Reconstituted systems with purified ERAD factors; in vitro ubiquitination assays; membrane composition manipulation; E2-E3 interaction assays bioRxivpreprint Medium bio_10.1101_2025.07.22.666085
2025 MARCH6 promotes ubiquitin-mediated degradation of ADAMTS4 in cardiomyocytes, thereby upregulating the downstream target SDC-1. This MARCHF6/ADAMTS4/SDC-1 axis inhibits lipid peroxidation and ferroptosis in myocardial ischemia-reperfusion injury. Co-immunoprecipitation; ubiquitination assays; MARCHF6 overexpression (AAV9 in mice); IRI mouse model; OGD/R cell model; ferroptosis markers Biochimica et biophysica acta. Molecular basis of disease Low 42155815

Source papers

Stage 0 corpus · 37 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Sterol homeostasis requires regulated degradation of squalene monooxygenase by the ubiquitin ligase Doa10/Teb4. eLife 167 23898401
2005 TEB4 is a C4HC3 RING finger-containing ubiquitin ligase of the endoplasmic reticulum. The Biochemical journal 149 15673284
2014 The E3 ubiquitin ligase MARCH6 degrades squalene monooxygenase and affects 3-hydroxy-3-methyl-glutaryl coenzyme A reductase and the cholesterol synthesis pathway. Molecular and cellular biology 145 24449766
2019 Unstable TTTTA/TTTCA expansions in MARCH6 are associated with Familial Adult Myoclonic Epilepsy type 3. Nature communications 123 31664039
2005 Membrane topology of the yeast endoplasmic reticulum-localized ubiquitin ligase Doa10 and comparison with its human ortholog TEB4 (MARCH-VI). The Journal of biological chemistry 119 16373356
2018 Coordinate regulation of mutant NPC1 degradation by selective ER autophagy and MARCH6-dependent ERAD. Nature communications 102 30202070
2022 The MARCHF6 E3 ubiquitin ligase acts as an NADPH sensor for the regulation of ferroptosis. Nature cell biology 78 35941365
2009 The E3 ubiquitin ligase TEB4 mediates degradation of type 2 iodothyronine deiodinase. Molecular and cellular biology 74 19651899
2018 MARCH6 and TRC8 facilitate the quality control of cytosolic and tail-anchored proteins. EMBO reports 67 29519897
2018 Cholesterol increases protein levels of the E3 ligase MARCH6 and thereby stimulates protein degradation. The Journal of biological chemistry 42 30545937
2015 A MARCH6 and IDOL E3 Ubiquitin Ligase Circuit Uncouples Cholesterol Synthesis from Lipoprotein Uptake in Hepatocytes. Molecular and cellular biology 38 26527619
2016 A Conserved C-terminal Element in the Yeast Doa10 and Human MARCH6 Ubiquitin Ligases Required for Selective Substrate Degradation. The Journal of biological chemistry 37 27068744
2020 The E3 ubiquitin ligase MARCHF6 as a metabolic integrator in cholesterol synthesis and beyond. Biochimica et biophysica acta. Molecular and cell biology of lipids 28 33049405
2020 The cholesterol synthesis enzyme lanosterol 14α-demethylase is post-translationally regulated by the E3 ubiquitin ligase MARCH6. The Biochemical journal 27 31904814
2014 Ubiquitin-specific protease 19 regulates the stability of the E3 ubiquitin ligase MARCH6. Experimental cell research 27 25088257
2020 The MARCH6-SQLE Axis Controls Endothelial Cholesterol Homeostasis and Angiogenic Sprouting. Cell reports 23 32755570
2021 MARCH6 promotes Papillary Thyroid Cancer development by destabilizing DHX9. International journal of biological sciences 21 34512155
2023 Marchf6 E3 ubiquitin ligase critically regulates endoplasmic reticulum stress, ferroptosis, and metabolic homeostasis in POMC neurons. Cell reports 20 37421621
2023 Cholesterol synthesis enzyme SC4MOL is fine-tuned by sterols and targeted for degradation by the E3 ligase MARCHF6. Journal of lipid research 18 36958722
2024 Doa10/MARCH6 architecture interconnects E3 ligase activity with lipid-binding transmembrane channel to regulate SQLE. Nature communications 14 38195637
2021 MARCH6 promotes hepatocellular carcinoma development through up-regulation of ATF2. BMC cancer 14 34273954
2019 Consulting prostate cancer cohort data uncovers transcriptional control: Regulation of the MARCH6 gene. Biochimica et biophysica acta. Molecular and cell biology of lipids 10 31422115
2023 The Brucella abortus Type IV Effector BspA Inhibits MARCH6-Dependent ERAD To Promote Intracellular Growth. Infection and immunity 9 37129527
2024 Delineation of the substrate recognition domain of MARCHF6 E3 ubiquitin ligase in the Ac/N-degron pathway and its regulatory role in ferroptosis. The Journal of biological chemistry 8 39216628
2025 MARCH6 suppresses Tembusu virus replication by targeting viral NS5 protein for TOLLIP-mediated selective autophagic degradation. Journal of virology 4 40511919
2024 A paREDOX in the control of cholesterol biosynthesis: Does the NADPH sensor and E3 ubiquitin ligase MARCHF6 protect mammalian cells during oxidative stress by controlling sterol biosynthesis? BioEssays : news and reviews in molecular, cellular and developmental biology 4 38760877
2025 March6 Protects Against Acute Kidney Injury by Suppressing Renal Tubular Epithelial Cell Ferroptosis Through the Destabilization of P53 and ACSL4 Proteins. Inflammation 3 40445517
2024 Development of a monoclonal antibody to study MARCH6, an E3 ligase that regulates proteins that control lipid homeostasis. Journal of lipid research 2 39306038
2026 MARCH6 Confers Protection Against Endoplasmic Reticulum Autophagy in Gliomas by Destabilizing FAM134B. Neurochemical research 0 41661358
2026 Loss of the E3 ubiquitin ligase MARCHF6 alters hepatic lipid metabolism and drives spontaneous hepatosteatosis. Molecular metabolism 0 42082151
2026 Unraveling MARCH6's role in cancer progression and metabolism from protein homeostasis to oncogenesis. Pharmacological research 0 42107511
2026 MARCHF6 regulates ferroptosis in myocardial ischemia-reperfusion injury via the ADAMTS4/SDC-1 pathway. Biochimica et biophysica acta. Molecular basis of disease 0 42155815
2026 MARCHF6 orchestrates hepatic lipid homeostasis by targeting SREBP1 for ER-associated degradation. Journal of hepatology 0 42173365
2025 The Ac/N-Degron Domain of MARCHF6 E3 Ubiquitin Ligase and Its Role in Regulating Ferroptosis. Cells 0 40643475
2025 First clinical diagnosis of FAME3 via commercial Long-Read sequencing reveals mosaic repeat expansion in MARCHF6 gene. Neurogenetics 0 40788430
2025 Identification of the Ac/N-degron recognition domain in the MARCHF6 E3 ubiquitin ligase. Methods in enzymology 0 40992841
2025 Novel, complex configurations of the MARCHF6 repeat expansion associated with progressive myoclonic epilepsy and familial adult myoclonic epilepsy. Brain communications 0 41268177

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