Affinage

RBM33

RNA-binding protein 33 · UniProt Q96EV2

Length
1170 aa
Mass
130.0 kDa
Annotated
2026-06-10
10 papers in source corpus 3 papers cited in narrative 4 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 4/4 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

RBM33 is an m6A-binding protein that couples direct RNA recognition to two distinct post-transcriptional control mechanisms: selective m6A demethylation and nuclear RNA export (PMID:37257451, PMID:35589130). In one axis, RBM33 forms a complex with the m6A demethylase ALKBH5, recruits it to specific m6A-marked mRNA substrates, and activates its catalytic activity by removing ALKBH5 SUMOylation, thereby directing demethylation of a defined subset of transcripts (PMID:37257451); through this route it stabilizes DDIT4 mRNA to promote autophagy in head-neck squamous cell carcinoma cells (PMID:37257451). In a parallel axis, RBM33 binds GC-rich elements in target transcripts and recruits the TREX-NXF1/NXT1 export machinery to drive nuclear export of high-GC-content RNAs, including the intronless lncRNA NORAD (PMID:35589130). Nucleotide-resolution mapping of RBM33 RNA-binding sites confirms direct, site-specific RNA engagement (PMID:38300798).

Mechanistic history

Synthesis pass · year-by-year structured walk · 4 steps
  1. 2022 High

    Establishing how RBM33 acts on RNA, a genome-wide screen placed it as a direct GC-rich RNA binder that channels high-GC transcripts into the nuclear export pathway.

    Evidence Genome-wide CRISPR screen with RNA binding and nuclear export assays identifying TREX-NXF1/NXT1 recruitment

    PMID:35589130

    Open questions at the time
    • Sequence/structural basis of GC-rich element recognition not defined
    • Breadth of the export-dependent transcriptome beyond NORAD not delineated
    • Relationship between the export function and m6A binding not resolved
  2. 2023 High

    To explain selective m6A demethylation, RBM33 was shown to act as a substrate-selecting cofactor for ALKBH5, recruiting and activating the demethylase by removing its SUMOylation.

    Evidence Co-IP, m6A-seq, SUMOylation assay, and functional rescue in HNSCC cells

    PMID:37257451

    Open questions at the time
    • Enzyme/mechanism stripping ALKBH5 SUMO not identified
    • Rules governing which m6A substrates are selected unclear
    • Whether RBM33 m6A binding and demethylation are coupled to its export role unknown
  3. 2023 Medium

    A concrete substrate-pathway axis was defined: RBM33-directed ALKBH5 demethylation stabilizes DDIT4 mRNA to promote autophagy in HNSCC.

    Evidence m6A-seq, mRNA stability assay, and knockdown/overexpression with autophagy readouts in HNSCC cells

    PMID:37257451

    Open questions at the time
    • Single cell-context study; generality across tissues untested
    • Other physiological substrates of the axis not catalogued
    • Quantitative contribution of DDIT4 stabilization to autophagy phenotype not isolated
  4. 2024 Medium

    Nucleotide-resolution binding maps confirmed direct, site-specific RNA engagement by RBM33 transcriptome-wide.

    Evidence PAR-CLIP-seq using a FLAG-RBM33 stable cell line in HEK293T

    PMID:38300798

    Open questions at the time
    • Protocol-focused report with limited functional interpretation
    • Binding-site motifs not linked to specific downstream outcomes here
    • Overlap between mapped sites and m6A/GC-rich functional targets not analyzed

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RBM33's two activities — GC-rich export and ALKBH5-dependent demethylation — are mechanistically integrated, and whether they operate on shared transcripts, remains unresolved.
  • No structural model of RBM33 RNA recognition
  • Coordination between export and demethylation functions undefined
  • Physiological scope beyond HNSCC and cultured cells unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003723 RNA binding 3 GO:0060090 molecular adaptor activity 2 GO:0098772 molecular function regulator activity 1
Localization
GO:0005634 nucleus 1
Pathway
R-HSA-8953854 Metabolism of RNA 2 R-HSA-9612973 Autophagy 1
Partners
ALKBH5NXF1NXT1
Complex memberships
RBM33-ALKBH5 complex

Evidence

Reading pass · 4 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2023 RBM33 is an m6A RNA-binding protein that forms a complex with the m6A demethylase ALKBH5, recruits ALKBH5 to m6A-marked substrate mRNAs, and activates ALKBH5 demethylase activity through removal of ALKBH5 SUMOylation, thereby directing selective demethylation of a subset of mRNA transcripts. Co-immunoprecipitation, m6A sequencing, identification of SUMOylation removal, mechanistic epistasis in HNSCC cells Molecular cell High 37257451
2023 RBM33 promotes autophagy in head-neck squamous cell carcinoma (HNSCC) cells by recruiting ALKBH5 to demethylate and stabilize DDIT4 mRNA, identifying a specific substrate-pathway axis downstream of RBM33–ALKBH5 complex activity. m6A-seq, mRNA stability assay, RBM33 knockdown/overexpression with autophagy readouts in HNSCC cells Molecular cell Medium 37257451
2022 RBM33 directly binds GC-rich elements in target transcripts and recruits components of the TREX-NXF1/NXT1 RNA export pathway to direct nuclear export of transcripts with high GC content, including the intronless lncRNA NORAD. Genome-wide CRISPR screen, RNA binding assays, nuclear export assays, identification of TREX-NXF1/NXT1 as recruited effectors Genes & development High 35589130
2024 RBM33 binds RNA at specific nucleotide-level sites in HEK293T cells, as demonstrated by PAR-CLIP-seq using a FLAG-RBM33 stable cell line. PAR-CLIP-seq (photoactivatable ribonucleoside-enhanced crosslinking and immunoprecipitation followed by next-generation sequencing) STAR protocols Medium 38300798

Source papers

Stage 0 corpus · 10 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2023 RBM33 is a unique m6A RNA-binding protein that regulates ALKBH5 demethylase activity and substrate selectivity. Molecular cell 49 37257451
2021 Circular RNA RBM33 contributes to cervical cancer progression via modulation of the miR-758-3p/PUM2 axis. Journal of molecular histology 22 33398465
2022 RBM33 directs the nuclear export of transcripts containing GC-rich elements. Genes & development 21 35589130
2021 Circular RNA RBM33 contributes to extracellular matrix degradation via miR-4268/EPHB2 axis in abdominal aortic aneurysm. PeerJ 13 34820156
2011 Expression, purification and characterization of refolded rBm-33 (pepsin inhibitor homolog) from Brugia malayi: a human Lymphatic Filarial parasite. Protein expression and purification 5 21745575
2012 Recombinant Brugia malayi pepsin inhibitor (rBm33) induced monocyte function and absence of apoptotic cell death: an in vitro study. Microbial pathogenesis 3 22484090
2017 Recombinant Brugia malayi pepsin inhibitor (rBm33) exploits host signaling events to regulate inflammatory responses associated with lymphatic filarial infections. Microbial pathogenesis 2 28942176
2012 Physicochemical characterization of an aspin (rBm-33) from a filarial parasite Brugia malayi against the important human aspartic proteases. Journal of enzyme inhibition and medicinal chemistry 2 22957693
2023 RBM33: A new regulator of N-6-methyladenosine (m6A) methylation. Molecular cell 1 37327770
2024 Protocol for detecting RBM33-binding sites in HEK293T cells using PAR-CLIP-seq. STAR protocols 0 38300798

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