Affinage

MTREX

Exosome RNA helicase MTR4 · UniProt P42285

Length
1042 aa
Mass
117.8 kDa
Annotated
2026-04-29
54 papers in source corpus 35 papers cited in narrative 36 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

MTREX (MTR4/SKIV2L2) is a nuclear DExH-box RNA helicase that serves as the central ATP-dependent unwinding engine and adaptor scaffold for the RNA exosome, channeling diverse RNA substrates—including pre-rRNAs, noncoding RNAs, aberrant mRNAs, replication-dependent histone mRNAs, and retrotransposon transcripts—into the exosome for processing or degradation. Its helicase core unwinds structured and polyadenylated RNA substrates, while a distinctive arch/KOW domain simultaneously contacts structured RNA and recruits adaptor proteins through short arch-interacting motifs (AIMs), enabling assembly of functionally distinct complexes: TRAMP (with Trf4/Air2), NEXT (with ZCCHC8/RBM7), and PAXT (with ZFC3H1), as well as ribosome biogenesis factors such as NOP53 and NVL2 (PMID:20566885, PMID:28883156, PMID:29844170, PMID:28733371, PMID:31358741). MTR4 is recruited to the exosome core through composite surfaces formed by MPP6 and RRP6/RRP47, and RNA-engaged MTR4 threads substrates through the exosome central channel to the DIS3 active site; the negative regulator NRDE2 locks MTR4 in a closed conformation that blocks exosome recruitment (PMID:29906447, PMID:25319414, PMID:30842217). Beyond RNA turnover, MTR4 controls nuclear RNA export, alternative splicing of metabolic and meiotic transcripts, R-loop resolution, subnuclear localization of exosome subunits, and chromatin state in oocytes and germ cells, with conditional knockout in mice causing infertility due to blocked meiotic initiation and oocyte growth failure (PMID:39378876, PMID:40097464, PMID:32024842, PMID:40651665).

Mechanistic history

Synthesis pass · year-by-year structured walk · 12 steps
  1. 1995 Medium

    Identification of MTREX as an active ATPase/helicase established that the HLA class III region encodes a novel RNA helicase, opening the question of its RNA substrates and biological role.

    Evidence Baculovirus-expressed SKI2W fusion protein demonstrated ATPase activity in vitro

    PMID:7610041

    Open questions at the time
    • No RNA substrates identified
    • No in vivo function demonstrated
    • Relationship to RNA exosome unknown
  2. 2010 High

    Crystal structures revealed that Mtr4 possesses a unique arch/KOW domain atop a DExH helicase core, with the arch required for rRNA processing independently of canonical helicase activity, establishing the modular architecture that underlies all subsequent mechanistic work.

    Evidence X-ray crystallography of yeast Mtr4 at 2.9 Å with in vitro RNA binding, arch deletion mutants tested in vivo for 5.8S rRNA processing

    PMID:20512111 PMID:20566885

    Open questions at the time
    • How the arch domain recognizes specific substrates or adaptors was unknown
    • No structure of MTR4 bound to the exosome
  3. 2012 High

    Reconstitution of TRAMP showed that Trf4/Air2 stimulates Mtr4 unwinding activity and that polyadenylation extends the range of substrates TRAMP can process, resolving how cofactors enhance the intrinsic helicase activity.

    Evidence In vitro RNA unwinding and ATPase assays with reconstituted TRAMP complex and defined substrates

    PMID:22532666

    Open questions at the time
    • Mechanism of stimulation at the structural level was not resolved
    • No human TRAMP reconstitution
  4. 2014 High

    Structural and functional studies showed that Mtr4 docks onto the exosome via a composite surface formed by the intertwined N-termini of Rrp6 and Rrp47, establishing the molecular basis for exosome engagement, while ratchet helix mutagenesis demonstrated the arch contributes directly to unwinding.

    Evidence X-ray crystallography of Rrp6/Rrp47/Mtr4 N-terminus complex, mutagenesis with in vivo growth and in vitro helicase assays

    PMID:25319414 PMID:25414331

    Open questions at the time
    • Full-length Mtr4-exosome structure not yet available
    • How Mtr4 threads RNA into the exosome channel was unknown
  5. 2017 High

    Multiple studies established MTR4 as the central scaffold for functionally distinct nuclear exosome-targeting complexes: PAXT (with ZFC3H1, targeting prematurely terminated and antisense RNAs), while adaptor recruitment occurs through arch-interacting motifs (AIMs) on the KOW domain that can simultaneously bind structured RNA, and MPP6 was shown to tether MTR4 to the exosome core and enable RNA channeling.

    Evidence Co-IP/RNA-seq identifying PAXT; crystal structures of Mtr4-Nop53 AIM and MPP6-exosome-Mtr4 complexes; NMR of dual RNA/AIM binding; B-cell proximity ligation for MTR4-senataxin cooperation

    PMID:28351885 PMID:28431250 PMID:28733371 PMID:28742025 PMID:28877463 PMID:28883156

    Open questions at the time
    • How mutually exclusive adaptor binding is regulated in cells was unclear
    • PAXT complex architecture not structurally resolved
    • Whether MTR4's role in somatic hypermutation is direct or indirect was not fully resolved
  6. 2018 High

    Cryo-EM of the 14-subunit human nuclear exosome captured RNA-engaged MTR4 threading substrate through the exosome channel to the DIS3 active site, and showed that ZCCHC8 stimulates MTR4 helicase activity through a binding mode distinct from yeast TRAMP, revealing how NEXT activates MTR4.

    Evidence Cryo-EM at 3.45 Å of human MTR4-exosome with RNA; crystal structure of ZCCHC8-MTR4 with in vitro ATPase/helicase assays

    PMID:29844170 PMID:29906447

    Open questions at the time
    • No structure of the complete NEXT or PAXT complex on the exosome
    • Conformational dynamics during RNA threading not captured
  7. 2019 High

    The arch domain was confirmed as a versatile, mutually exclusive adaptor-recruitment platform in the human system (binding NVL and ZCCHC8 AIMs), while NRDE2 was identified as a negative regulator that locks MTR4 in a closed conformation to block exosome, CBC, and ZFC3H1 interactions, establishing conformational regulation of MTR4 activity.

    Evidence Competition binding assays, NMR, mutagenesis for arch-AIM interactions; co-IP, structural analysis, and mESC self-renewal assay for NRDE2-MTR4

    PMID:30842217 PMID:31358741

    Open questions at the time
    • How NRDE2-mediated inhibition is relieved in cells is unknown
    • Structural basis of the closed conformation not fully resolved
  8. 2020 Medium

    MTR4 was shown to influence alternative splicing of glycolytic gene pre-mRNAs (GLUT1, PKM2) in hepatocellular carcinoma, extending its functional scope beyond RNA decay to co-transcriptional RNA processing relevant to metabolic reprogramming.

    Evidence siRNA knockdown with RT-PCR splicing assays and ChIP showing c-Myc drives MTR4 transcription

    PMID:32024842

    Open questions at the time
    • Whether MTR4 directly contacts these pre-mRNAs or acts indirectly is unresolved
    • Single cancer cell line context limits generalizability
  9. 2021 Medium

    Post-translational regulation of MTR4 was identified: SYVN1 ubiquitinates MTR4 under methionine restriction to reduce its levels, while NVL2 was shown to remodel the MTR4-exosome complex by dissociating SPF30, and hnRNPH1 was identified as an RNA-independent MTR4 partner controlling NEAT1v2 lncRNA stability.

    Evidence Co-IP with ubiquitination assays (SYVN1); NVL2 ATPase-dead mutant trapping SPF30; co-IP and knockdown for hnRNPH1-MTR4

    PMID:33422691 PMID:33859984 PMID:34470577

    Open questions at the time
    • Ubiquitination site(s) on MTR4 not mapped
    • SPF30 role in rRNA processing via MTR4 not fully dissected
    • hnRNPH1 binding interface on MTR4 not defined
  10. 2022 Medium

    HDX-MS revealed that the arch/KOW domain contacts RNA in a structure- and length-dependent manner driving MTR4 into a closed conformation, while the AIM-dependent NOP53-MTR4 interaction was shown to be specifically required for late 5.8S rRNA maturation; MPP6 and RRP6 pathways were shown to recruit MTR4 non-equivalently for distinct RNA substrate classes.

    Evidence HDX-MS with functional unwinding assays; AIM mutant analysis with Northern blots for rRNA processing; RNA-seq and reconstitution comparing MPP6/RRP6 pathways

    PMID:35380691 PMID:35902094 PMID:36403484

    Open questions at the time
    • Closed vs. open conformation dynamics during catalysis not resolved
    • How substrate selectivity differs between MPP6- and RRP6-recruited MTR4 is unclear
  11. 2024 High

    Conditional knockouts in mice established MTR4 as essential for oocyte developmental competence (controlling maternal RNA processing, nuclear export, chromatin state, and nucleolus formation) and revealed MTR4-hnRNPK surveillance of aberrant 3' extended transcripts (3XTs) whose protein products form toxic condensates.

    Evidence Oocyte-specific Mtr4 KO with RNA-seq, ChIP-seq, and live imaging; co-IP, long-read RNA-seq, and condensate imaging for hnRNPK-MTR4-3XT pathway

    PMID:39378876 PMID:39419981

    Open questions at the time
    • How MTR4 distinguishes 3XTs from normal polyadenylated mRNAs is not defined
    • Whether MTR4 directly regulates chromatin or acts through RNA intermediates in oocytes is unresolved
  12. 2025 High

    Germ cell-specific Mtr4 KO showed MTR4/exosome represses meiotic gene transcripts at the pre-meiotic stage and is required for meiotic initiation and male fertility; MTR4 also controls nucleolar retention of exosome subunits independently of TRAMP/NEXT/PAXT, and TRAMP assembly with Cid14 was shown to activate Mtr4 unwinding through its disordered N-terminus.

    Evidence Conditional KO with RNA-seq and histology; nucleolar quantitative proteomics with imaging; reconstituted S. pombe TRAMP with HDX-MS and mutagenesis

    PMID:40097464 PMID:40519184 PMID:40651665

    Open questions at the time
    • How MTR4 directs exosome subunit nucleolar localization mechanistically is unknown
    • Whether N-terminal disorder-mediated TRAMP activation is conserved in human TRAMP

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key open questions include: the structural basis for how MTR4 selects among competing adaptor complexes in vivo, the full repertoire of conformational states during RNA threading and exosome handoff, and whether MTR4-dependent chromatin and 3D genome organization effects are direct consequences of RNA turnover or involve additional mechanisms.
  • No structure of complete human PAXT or NEXT on the exosome
  • In vivo dynamics of adaptor switching not captured
  • Causal relationship between RNA surveillance and chromatin/3D genome effects not resolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140657 ATP-dependent activity 5 GO:0003723 RNA binding 4 GO:0140098 catalytic activity, acting on RNA 4
Localization
GO:0005634 nucleus 3 GO:0005654 nucleoplasm 2 GO:0005730 nucleolus 1
Pathway
R-HSA-8953854 Metabolism of RNA 6 R-HSA-392499 Metabolism of proteins 4 R-HSA-74160 Gene expression (Transcription) 2
Partners
EXOSC10HNRNPKMPP6NOP53NRDE2NVL2ZCCHC8ZFC3H1
Complex memberships
NEXTPAXTTRAMPnuclear RNA exosome

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1995 Human SKI2W (MTREX/SKIV2L2) was cloned and characterized as a novel RNA helicase in the HLA class III region; the fusion protein expressed in insect cells demonstrated ATPase activity, establishing it as an active helicase. Baculovirus expression, ATPase activity assay, sequence analysis Nucleic Acids Research Medium 7610041
2010 Crystal structure of Saccharomyces cerevisiae Mtr4 at 2.9 Å resolution revealed a central DExH ATPase core, an arch/stalk domain with a KOW/beta-barrel domain that binds RNA in vitro, and that the DExH core (not the arch) mediates interaction with Trf4-Air2 in the TRAMP complex. X-ray crystallography (2.9 Å), in vitro RNA binding assay, co-complex reconstitution Proceedings of the National Academy of Sciences of the United States of America High 20566885
2010 Crystal structure of Mtr4 revealed a novel arch domain (conserved in Mtr4 and Ski2) that is required for proper 5.8S rRNA processing in vivo and in vitro, and functions independently of canonical helicase activity. X-ray crystallography, in vivo rRNA processing assay, in vitro helicase assay, arch deletion mutants The EMBO Journal High 20512111
2011 SKIV2L2 (MTREX) protein localizes to the nuclei of round spermatids in mice and exhibits RNA-binding and ATPase activities. Proteomic identification, subcellular fractionation/immunostaining, ATPase activity assay, RNA-binding assay The Journal of reproduction and development Medium 21467735
2012 The TRAMP complex (Trf4/Air2/Mtr4) robustly unwinds RNA duplexes; Trf4/Air2 significantly stimulates Mtr4 unwinding activity independently of ongoing polyadenylation, and polyadenylation enables TRAMP to unwind substrates that Mtr4 alone cannot, with optimal activity on substrates with an adenylate 3' single-stranded region. In vitro RNA unwinding assay, ATPase assay, reconstituted TRAMP complex Proceedings of the National Academy of Sciences of the United States of America High 22532666
2013 In fission yeast, the Mtr4-like protein Mtl1 (ortholog of MTREX) forms a core module with Red1 that promotes RNA degradation and heterochromatin assembly, and also forms Red1-independent interactions with splicing-factor-associated proteins Nrl1 and Ctr1, with Ctr1 functioning in processing intron-containing telomerase RNA. Co-immunoprecipitation, genetic epistasis, RNA-seq, in vivo functional assays Cell High 24210919
2014 The N-terminal domains of Rrp6 and Rrp47 form an intertwined structural unit that creates a composite conserved surface groove binding the N-terminus of Mtr4; Mtr4 binding to the exosome core requires both Rrp6 and Rrp47 in vitro; mutations at this interface disrupt the interaction and inhibit growth. X-ray crystallography, in vitro binding assay, site-directed mutagenesis, in vivo growth assay The EMBO Journal High 25319414
2014 Mtr4 ratchet helix residues modulate helicase activity and affinity for polyadenylated substrates; combining arch domain deletion with ratchet helix mutations abolishes helicase activity in vitro and produces a lethal phenotype in vivo, revealing that the arch domain contributes to RNA unwinding. In vitro helicase assay, ATPase assay, site-directed mutagenesis, in vivo growth assay Nucleic Acids Research High 25414331
2015 NVL2 AAA-ATPase interacts with the MTR4-exosome complex and uses its ATPase activity to dissociate WDR74 (a WD-repeat protein with similarity to yeast Nsa1) from the complex; WDR74 knockdown decreases 60S ribosome levels, implying NVL2 remodels the MTR4-exosome complex during pre-ribosomal particle maturation. Proteomic screen, co-immunoprecipitation, ATPase mutant analysis, siRNA knockdown with ribosome profiling Biochemical and Biophysical Research Communications Medium 26456651
2017 MTR4 forms a distinct complex with ZFC3H1 (PAXT complex) that is separate from NEXT; knockdown of either MTR4 or ZFC3H1 causes prematurely terminated RNAs and upstream antisense RNAs to accumulate in the nucleus and cytoplasm, where they associate with active ribosomes and cause global repression of translation. Co-immunoprecipitation, RNA-seq, polysome profiling, siRNA knockdown, subcellular fractionation Genes & Development High 28733371
2017 MTR4 helicase acts in close physical proximity with senataxin and the RNA exosome to process noncoding RNAs at the immunoglobulin locus, determining strand-specific distribution of AID-induced DNA mutations in B cells. Proximity ligation, ChIP, genetic knockout, DNA mutation analysis Cell Medium 28431250
2017 The crystal structure of a 12-subunit nuclear exosome with Mpp6 bound to RNA shows the central region of Mpp6 bound to the exosome core (via Rrp40), positioning its Mtr4-recruitment domain adjacent to Rrp6 and the exosome channel; Mpp6 is required for Mtr4 to extend the RNA trajectory through the exosome core. X-ray crystallography (3.3 Å), in vitro RNA decay assay, biochemical reconstitution eLife High 28742025
2017 Mpp6 binds Rrp40 in the exosome core via conserved linear motifs and is required for Mtr4 to channel RNA substrates from the helicase into the exosome core; the Rrp40 tryptophan residue at the interface is mutated in pontocerebellar hypoplasia patients. X-ray crystallography (3.2 Å), in vitro RNA channeling assay, site-directed mutagenesis Cell Reports High 28877463
2017 Mtr4 interacts directly with Nop53 (a pre-60S ribosome biogenesis factor) via an arch-interacting motif (AIM); the 3.2 Å crystal structure of Mtr4-Nop53 reveals that the KOW domain of Mtr4 recognizes the AIM sequence; NMR shows the KOW domain can simultaneously bind an AIM-containing protein and a structured RNA at adjacent surfaces. X-ray crystallography (3.2 Å), NMR, in vitro binding assay RNA High 28883156
2017 SKIV2L2 (MTREX) depletion in murine cells impairs G2/M progression, causes accumulation of mitotic cells, and leads to elevated replication-dependent histone mRNAs, identifying these as MTR4-surveillance targets whose accumulation may impede mitotic progression. siRNA knockdown, cell-cycle analysis (propidium iodide), RNA-seq, quantitative RT-PCR RNA Medium 28351885
2018 Cryo-EM structure (3.45 Å) of a human MTR4-containing 14-subunit nuclear RNA exosome reveals RNA-engaged MTR4 helicase atop the non-catalytic core with RNA captured in the central channel and DIS3 active site; MPP6 tethers MTR4 to the exosome through contacts to the RecA domains of MTR4; RNA-engaged MTR4 displaces EXOSC10's catalytic module and cofactor C1D. Cryo-EM (3.45 Å), in vitro RNA unwinding and degradation assay, reconstitution of human, yeast, and S. pombe exosomes Cell High 29906447
2018 The NEXT complex subunit ZCCHC8 contains a C-terminal domain that binds the helicase core of MTR4 (distinct from yeast Trf4/Air2 binding mode) and stimulates MTR4 helicase and ATPase activities; uridine-rich substrates are preferred by RBM7/ZCCHC8, while optimal unwinding requires polyadenylated 3' ends. X-ray crystallography, in vitro ATPase/helicase assay, site-directed mutagenesis Proceedings of the National Academy of Sciences of the United States of America High 29844170
2019 Human MTR4 arch domain recruits nuclear exosome adaptors NVL (ribosome processing) and ZCCHC8 (snRNA decay) via short linear arch-interacting motifs (AIMs) in their unstructured regions; NVL and ZCCHC8 bind the arch in a mutually exclusive manner, demonstrating the versatility of the arch domain as an adaptor recruitment platform. Co-immunoprecipitation, pulldown, NMR/structural analysis, competition binding assays, mutagenesis Nature Communications High 31358741
2019 NRDE2 forms a 1:1 complex with MTR4 via a conserved MTR4-interacting domain (MID); NRDE2 localizes in nuclear speckles and inhibits MTR4 recruitment and RNA degradation by locking MTR4 in a closed conformation and blocking its interaction with the exosome, CBC, and ZFC3H1; MID deletion results in loss of self-renewal of mouse embryonic stem cells. Co-immunoprecipitation, structural analysis, siRNA knockdown, RNA stability assay, mESC self-renewal assay Genes & Development High 30842217
2020 MTR4 ensures correct alternative splicing of pre-mRNAs of glycolytic genes GLUT1 and PKM2 in hepatocellular carcinoma cells; c-Myc binds the MTR4 promoter and drives MTR4 expression, linking MTR4 to cancer metabolic reprogramming. siRNA knockdown, splicing assay (RT-PCR), ChIP, reporter assay, RNA-seq Nature Communications Medium 32024842
2021 NVL2 interacts with the MTR4-exosome complex and mediates the dissociation of SPF30 (a Tudor domain splicing factor) from the complex via ATPase activity; SPF30 interacts with MTR4 and the exosome core through its N- and C-terminal regions and participates in pre-rRNA processing, pre-mRNA splicing, and snoRNA biogenesis. Co-immunoprecipitation, proteomic interactome analysis, siRNA knockdown, rRNA processing assay The International Journal of Biochemistry & Cell Biology Medium 33422691
2021 hnRNPH1 associates with MTR4 in an RNA-independent manner and localizes to nuclear speckles; the hnRNPH1-MTR4 complex controls NEAT1v2 lncRNA stability, and depletion of hnRNPH1 enhances NEAT1v2-mediated IL8 mRNA expression. Co-immunoprecipitation, siRNA knockdown, qRT-PCR, nuclear fractionation RNA Biology Medium 34470577
2021 SYVN1 acts as an E3 ubiquitin ligase that ubiquitinates MTR4 under methionine restriction, reducing MTR4 protein levels and promoting nuclear export of MAT2A mRNA in glioma cells. Co-immunoprecipitation, ubiquitination assay, cytoplasmic-nuclear fractionation, Western blotting Frontiers in Cell and Developmental Biology Medium 33859984
2022 PICT1/NOP53 (mammalian ortholog of yeast Nop53) interacts with MTR4 and the exosome in an AIM-dependent manner and is required for two distinct pre-rRNA processing steps during 60S ribosome biogenesis; MTR4 and exosome recruitment via AIM is required specifically for late 12S→5.8S rRNA maturation. Co-immunoprecipitation, AIM mutant analysis, siRNA knockdown, rRNA processing assay, Northern blot Biochemical and Biophysical Research Communications Medium 36403484
2022 MTR4 and APE1 interact physically in a manner stimulated by cisplatin and 5-FU treatment, partially mediated through lysine residues in the APE1 N-terminal region and nucleic acids; depletion of either APE1 or MTR4 results in R-loop formation and activation of the ATM-p53-p21 DNA damage response pathway. Co-immunoprecipitation, siRNA knockdown, R-loop detection (S9.6 antibody), immunofluorescence, Western blot The FEBS Journal Medium 36310106
2022 MTR4-exosome interaction via MPP6 is essential for MPP6-dependent RNA decay; MPP6 and RRP6 are functionally redundant for decay of certain poly(A)+ transcripts, but MTR4 recruitment by MPP6 and by RRP6 are not equivalent, suggesting the MPP6-incorporated MTR4-exosome complex is one of multiple alternative exosome configurations. siRNA knockdown, RNA-seq, in vitro reconstitution, co-immunoprecipitation Nucleic Acids Research Medium 35902094
2022 HDX-MS revealed that Mtr4 arch (KOW/fist domain) contacts RNA in a structure- and length-dependent manner distinct from the conserved helicase core contacts; these arch-RNA interactions are important for RNA unwinding and drive Mtr4 into a closed conformation with reduced arch dynamics. Hydrogen-deuterium exchange mass spectrometry (HDX-MS), RNA affinity assay, in vitro unwinding assay Nucleic Acids Research Medium 35380691
2023 The conserved SLYΦ C-terminal motif of Mtr4 is critical for helicase activity and for RNA exosome cooperation; mutations in the C-terminus decrease RNA unwinding and impair Rrp44-mediated RNA degradation in vitro, with genetic interactions indicating importance for exosome function in vivo. In vitro helicase assay, RNA degradation assay, genetic interaction analysis, in vivo growth assay Biochemistry Medium 38085597
2023 A multiple myeloma patient-derived missense mutation in EXOSC2 (p.Met40Thr), modeled into yeast Rrp4 as M68T, disrupts the direct interaction between the exosome cap subunit and Mtr4; rrp4-M68T cells show accumulation of RNA exosome target RNAs and genetic interactions with specific mtr4 mutants. Structural modeling, co-immunoprecipitation, genetic epistasis, RNA qRT-PCR G3 (Bethesda, Md.) Medium 36861343
2024 MTR4 is required in mouse oocytes for post-transcriptional processing of maternal RNAs, their nuclear export, and accumulation of properly processed transcripts; Mtr4 knockout oocytes fail to grow to normal size, have disrupted non-canonical H3K4me3 establishment, and fail to form nucleolus-like structures, establishing MTR4-dependent RNA surveillance as a checkpoint for oocyte developmental competence. Conditional knockout (Mtr4 oocyte-specific), live imaging, RNA-seq, ChIP-seq, immunostaining Developmental Cell High 39378876
2024 MTR4 associates with hnRNPK to form a complex that surveils 3' eXtended Transcripts (3XTs) — intronic polyadenylated read-through transcripts with multiple exons; the hnRNPK-MTR4-RNA exosome pathway degrades aberrant 3XT-derived proteins and prevents formation of aberrant condensates (KeXT bodies). Co-immunoprecipitation, long-read direct RNA sequencing, 3' RNA-seq, siRNA knockdown, condensate imaging Nature Communications High 39419981
2025 MTR4 regulates the localization of RNA exosome subunits within the nucleus; MTR4 depletion causes translocation of exosome subunits from the nucleolus to the nucleoplasm in a manner specific to MTR4 and not dependent on other cofactors of TRAMP, PAXT, or NEXT complexes. Nucleolar quantitative proteomics, immunostaining, fluorescence tagging, siRNA knockdown Molecular & Cellular Proteomics Medium 40651665
2025 Germ cell-specific Mtr4 knockout in mice causes male infertility with complete block at meiotic initiation; MTR4/exosome represses meiotic genes (shorter, fewer introns) through RNA degradation during the pre-meiotic stage, while ensuring mitotic gene expression, and regulates alternative splicing of meiotic genes; replication-dependent histone mRNAs and polyadenylated retrotransposon RNAs are MTR4/exosome targets in germ cells. Conditional knockout, RNA-seq, alternative splicing analysis, Northern blot, histology Nature Communications High 40097464
2025 MTR4 (MTREX) depletion causes accumulation of enhancer-associated RNAs (eRNAs) and PROMPTs, increases cohesin levels at sites of ncRNA accumulation, and alters 3D enhancer-promoter chromatin contacts, with MTR4 loss increasing anchor-point contacts and decreasing intra-loop contacts, suggesting MTR4 facilitates cohesin-mediated loop extrusion. ChIP-seq, chromatin conformation capture (Hi-C/4C), RNA-seq, siRNA knockdown bioRxivpreprint Medium
2025 TRAMP assembly with Cid14 (S. pombe Trf4 ortholog) activates Mtr4 helicase activity: S. pombe Mtr4 alone has RNA-stimulated ATPase activity but cannot unwind a model RNA substrate; TRAMP formation, specifically through interactions with the intrinsically disordered N-terminus of Cid14, restores unwinding activity; competition between RNA-binding sites on Mtr4 and Air2 zinc knuckles drives tRNA transfer between TRAMP catalytic sites. In vitro helicase and ATPase assay, HDX-MS, site-directed mutagenesis, reconstituted complex Biochemistry High 40519184
2025 KMT2B methyltransferase methylates MTR4 under methionine starvation conditions, promoting its ubiquitin-mediated degradation; reduced MTR4 facilitates nuclear export of SLC1A5 mRNA in glioma cells, activating mTORC1 signaling. Co-immunoprecipitation, methylation assay, ubiquitination assay, siRNA knockdown, cytoplasmic-nuclear fractionation, qRT-PCR Amino Acids Low 41428109

Source papers

Stage 0 corpus · 54 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2013 Mtr4-like protein coordinates nuclear RNA processing for heterochromatin assembly and for telomere maintenance. Cell 157 24210919
2010 Structural analysis reveals the characteristic features of Mtr4, a DExH helicase involved in nuclear RNA processing and surveillance. Proceedings of the National Academy of Sciences of the United States of America 122 20566885
2018 Helicase-Dependent RNA Decay Illuminated by a Cryo-EM Structure of a Human Nuclear RNA Exosome-MTR4 Complex. Cell 119 29906447
2017 An Mtr4/ZFC3H1 complex facilitates turnover of unstable nuclear RNAs to prevent their cytoplasmic transport and global translational repression. Genes & development 109 28733371
2010 The crystal structure of Mtr4 reveals a novel arch domain required for rRNA processing. The EMBO journal 101 20512111
2014 The exosome-binding factors Rrp6 and Rrp47 form a composite surface for recruiting the Mtr4 helicase. The EMBO journal 94 25319414
2011 MTR4, a putative RNA helicase and exosome co-factor, is required for proper rRNA biogenesis and development in Arabidopsis thaliana. The Plant journal : for cell and molecular biology 85 21682783
2020 MTR4 drives liver tumorigenesis by promoting cancer metabolic switch through alternative splicing. Nature communications 79 32024842
2012 RNA unwinding by the Trf4/Air2/Mtr4 polyadenylation (TRAMP) complex. Proceedings of the National Academy of Sciences of the United States of America 61 22532666
2011 Air1 zinc knuckles 4 and 5 and a conserved IWRXY motif are critical for the function and integrity of the Trf4/5-Air1/2-Mtr4 polyadenylation (TRAMP) RNA quality control complex. The Journal of biological chemistry 61 21878619
2018 Structural basis for MTR4-ZCCHC8 interactions that stimulate the MTR4 helicase in the nuclear exosome-targeting complex. Proceedings of the National Academy of Sciences of the United States of America 56 29844170
2017 Nuclear Proximity of Mtr4 to RNA Exosome Restricts DNA Mutational Asymmetry. Cell 54 28431250
2017 Structure and reconstitution of yeast Mpp6-nuclear exosome complexes reveals that Mpp6 stimulates RNA decay and recruits the Mtr4 helicase. eLife 50 28742025
1995 Human helicase gene SKI2W in the HLA class III region exhibits striking structural similarities to the yeast antiviral gene SKI2 and to the human gene KIAA0052: emergence of a new gene family. Nucleic acids research 50 7610041
2017 Mpp6 Incorporation in the Nuclear Exosome Contributes to RNA Channeling through the Mtr4 Helicase. Cell reports 48 28877463
2019 NRDE2 negatively regulates exosome functions by inhibiting MTR4 recruitment and exosome interaction. Genes & development 44 30842217
2019 The MTR4 helicase recruits nuclear adaptors of the human RNA exosome using distinct arch-interacting motifs. Nature communications 44 31358741
2017 Structural insights into the interaction of the nuclear exosome helicase Mtr4 with the preribosomal protein Nop53. RNA (New York, N.Y.) 37 28883156
2007 Mutations in gfpt1 and skiv2l2 cause distinct stage-specific defects in larval melanocyte regeneration in zebrafish. PLoS genetics 35 17542649
2007 Trypanosome MTR4 is involved in rRNA processing. Nucleic acids research 33 17940093
2006 The AAA-ATPase NVL2 is a component of pre-ribosomal particles that interacts with the DExD/H-box RNA helicase DOB1. Biochemical and biophysical research communications 33 16782053
2014 The Mtr4 ratchet helix and arch domain both function to promote RNA unwinding. Nucleic acids research 32 25414331
1994 HLA-DOB1 "low-resolution' typing by PCR amplification with sequence-specific primers (PCR-SSP). European journal of immunogenetics : official journal of the British Society for Histocompatibility and Immunogenetics 31 9098454
2013 Cotranscriptional recruitment of RNA exosome cofactors Rrp47p and Mpp6p and two distinct Trf-Air-Mtr4 polyadenylation (TRAMP) complexes assists the exonuclease Rrp6p in the targeting and degradation of an aberrant messenger ribonucleoprotein particle (mRNP) in yeast. The Journal of biological chemistry 29 24047896
1999 HLA DOA1 and DOB1 loci in Honduran women with cervical dysplasia and invasive cervical carcinoma and their relationship to human papillomavirus infection. Human biology 25 10380373
2015 AAA-ATPase NVL2 acts on MTR4-exosome complex to dissociate the nucleolar protein WDR74. Biochemical and biophysical research communications 20 26456651
2012 Genetic interactions suggest multiple distinct roles of the arch and core helicase domains of Mtr4 in Rrp6 and exosome function. Nucleic acids research 18 23143101
2021 Mtr4 RNA helicase structures and interactions. Biological chemistry 17 33857361
2021 SYVN1-MTR4-MAT2A Signaling Axis Regulates Methionine Metabolism in Glioma Cells. Frontiers in cell and developmental biology 14 33859984
2021 hnRNPH1-MTR4 complex-mediated regulation of NEAT1v2 stability is critical for IL8 expression. RNA biology 12 34470577
2022 APE1 interacts with the nuclear exosome complex protein MTR4 and is involved in cisplatin- and 5-fluorouracil-induced RNA damage response. The FEBS journal 9 36310106
2023 The RNA helicases Dbp2 and Mtr4 regulate the expression of Xrn1-sensitive long non-coding RNAs in yeast. Frontiers in RNA research 8 37667796
2017 Loss of the RNA helicase SKIV2L2 impairs mitotic progression and replication-dependent histone mRNA turnover in murine cell lines. RNA (New York, N.Y.) 8 28351885
2011 Localization of a novel RNA-binding protein, SKIV2L2, to the nucleus in the round spermatids of mice. The Journal of reproduction and development 8 21467735
2024 RNA surveillance by the RNA helicase MTR4 determines volume of mouse oocytes. Developmental cell 7 39378876
2022 Hydrogen-deuterium exchange mass spectrometry of Mtr4 with diverse RNAs reveals substrate-dependent dynamics and interfaces in the arch. Nucleic acids research 7 35380691
2022 MPP6 stimulates both RRP6 and DIS3 to degrade a specified subset of MTR4-sensitive substrates in the human nucleus. Nucleic acids research 7 35902094
2022 Using hydrogen-deuterium exchange mass spectrometry to characterize Mtr4 interactions with RNA. Methods in enzymology 7 35965017
2021 Interactome analysis of the Tudor domain-containing protein SPF30 which associates with the MTR4-exosome RNA-decay machinery under the regulation of AAA-ATPase NVL2. The international journal of biochemistry & cell biology 7 33422691
2020 Exploration of Salmonella effector mutant strains on MTR4 and RRP6 degradation. Bioscience trends 5 32350160
2016 Mutations in Mtr4 Structural Domains Reveal Their Important Role in Regulating tRNAiMet Turnover in Saccharomyces cerevisiae and Mtr4p Enzymatic Activities In Vitro. PloS one 5 26820724
2014 Certain adenylated non-coding RNAs, including 5' leader sequences of primary microRNA transcripts, accumulate in mouse cells following depletion of the RNA helicase MTR4. PloS one 5 24926684
2023 In vivo characterization of the critical interaction between the RNA exosome and the essential RNA helicase Mtr4 in Saccharomyces cerevisiae. G3 (Bethesda, Md.) 4 36861343
2022 Purification and characterization of Mtr4 and TRAMP from S. cerevisiae. Methods in enzymology 3 35965015
2022 MTR4 adaptor PICT1 functions in two distinct steps during pre-rRNA processing. Biochemical and biophysical research communications 3 36403484
2023 Conserved Residues at the Mtr4 C-Terminus Coordinate Helicase Activity and Exosome Interactions. Biochemistry 2 38085597
2025 TRAMP assembly alters the conformation and RNA binding of Mtr4 and Trf4-Air2. Proceedings of the National Academy of Sciences of the United States of America 1 39752526
2025 The nuclear exosome co-factor MTR4 shapes the transcriptome for meiotic initiation. Nature communications 1 40097464
2025 Nucleolar Proteomics Revealed the Regulation of RNA Exosome Localization by MTR4. Molecular & cellular proteomics : MCP 1 40651665
2011 A zebrafish SKIV2L2-enhancer trap line provides a useful tool for the study of peripheral sensory circuit development. Gene expression patterns : GEP 1 21742057
2025 N-Terminus of Cid14 Activates RNA Unwinding by Mtr4 in the Schizosaccharomyces pombe TRAMP Complex. Biochemistry 0 40519184
2025 MTR4 methylation-dependent degradation activates mTORC1 signaling to promote glioma cell survival under methionine starvation. Amino acids 0 41428109
2024 TRAMP assembly alters the conformation and RNA binding of Mtr4 and Trf4-Air2. bioRxiv : the preprint server for biology 0 39211223
2024 The MTR4/hnRNPK complex surveils aberrant polyadenylated RNAs with multiple exons. Nature communications 0 39419981