Affinage

RAB33B

Ras-related protein Rab-33B · UniProt Q9H082

Length
229 aa
Mass
25.7 kDa
Annotated
2026-06-10
24 papers in source corpus 18 papers cited in narrative 18 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

RAB33B is a medial-Golgi-resident small GTPase that coordinates intra-Golgi membrane traffic, autophagosome biogenesis, and post-Golgi cargo delivery (PMID:9512502, PMID:20163571, PMID:32960676, PMID:35521520). At the Golgi it operates within a Rab cascade: GTP-bound RAB33B recruits the Ric1-Rgp1 GEF to activate trans-Golgi RAB6A, and RAB33B acts downstream of RAB6 to drive intra-Golgi retrograde trafficking, being required for retrograde toxin transport from trans to cis Golgi and ER (PMID:20163571, PMID:23091056). Its GTP-loaded form engages effectors GM130, rabaptin-5, and rabex-5 (PMID:11718716). In autophagy, GTP-bound RAB33B directly binds the coiled-coil domain of ATG16L1—a noncanonical RAB-binding protein that stabilizes RAB33B in an active conformation independent of nucleotide exchange—to recruit the ATG12-ATG5-ATG16L1 complex to phagophores, where this interaction is required for LC3 lipidation and autophagosome formation (PMID:18448665, PMID:26975471, PMID:32960676). Upon starvation RAB33B translocates from the Golgi to phagophores, a relocation supported by a functional LIR motif mediating GATE16 binding (PMID:32960676, PMID:40855209). RAB33B is inactivated by multiple GTPase-activating proteins—OATL1, which uses ATG8 as a scaffold to regulate autophagosome-lysosome fusion, RUTBC1, and TBC1D22 scaffolded by ACBD3 at the medial Golgi (PMID:21383079, PMID:21808068, PMID:28777890). In cell migration, RAB33B interacts with the exocyst subunit Exoc6 to deliver integrins to focal adhesions and modulate adhesion turnover (PMID:35521520). RAB33B missense and truncating mutations cause protein instability and Golgi mislocalization underlying Dyggve-Melchior-Clausen/Smith-McCort dysplasia (PMID:22652534, PMID:41506134).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 1998 High

    Established where RAB33B resides, placing it at the medial Golgi and implicating it in intra-Golgi transport.

    Evidence Immunofluorescence co-localization with alpha-mannosidase II and immunoelectron microscopy

    PMID:9512502

    Open questions at the time
    • No effectors or regulators identified
    • Functional role inferred from localization only
  2. 2001 Medium

    Identified the first GTP-dependent effectors and showed RAB33B activity controls intra-Golgi and Golgi-to-ER traffic.

    Evidence Microinjection of GTPase-deficient mutants and GST pulldown with MS identification of GM130, rabaptin-5, rabex-5

    PMID:11718716

    Open questions at the time
    • Functional significance of individual effector interactions not dissected
    • GEF/GAP regulators unknown
  3. 2008 High

    Connected RAB33B to autophagy by showing GTP-dependent binding to ATG16L modulates autophagosome formation.

    Evidence Reciprocal Co-IP, GTPase-deficient mutant overexpression, LC3 lipidation and p62 degradation assays, dominant-negative domain expression

    PMID:18448665

    Open questions at the time
    • Structural basis of RAB33B-ATG16L binding unresolved
    • Mechanism linking Golgi pool to autophagy unclear
  4. 2010 High

    Positioned RAB33B in a Rab cascade downstream of RAB6 governing intra-Golgi retrograde trafficking.

    Evidence Sequential siRNA knockdowns, GTP-restricted mutant overexpression, Golgi enzyme distribution imaging, Shiga toxin transport assay

    PMID:20163571

    Open questions at the time
    • Molecular link between RAB33B and RAB6 not identified at this stage
    • Effectors mediating retrograde transport unknown
  5. 2011 High

    Identified GAPs that inactivate RAB33B, including an autophagy-linked GAP that uses ATG8 as a scaffold to control autophagosome maturation.

    Evidence In vitro GAP activity assays, mutagenesis of catalytic residue, Co-IP, knockdown, autophagosome-lysosome fusion assay (OATL1 and RUTBC1 studies)

    PMID:21383079 PMID:21808068

    Open questions at the time
    • Relative contribution of multiple GAPs in vivo unclear
    • Spatial regulation of GAP recruitment partially defined
  6. 2012 High

    Defined the molecular link in the Golgi Rab cascade and the disease relevance of nucleotide binding.

    Evidence Ric1-Rgp1 binding/GEF assays; exome sequencing with Western blot and IF of patient cells

    PMID:22652534 PMID:23091056

    Open questions at the time
    • Single family for disease link in 2012
    • Mechanism connecting GTPase defect to skeletal dysplasia phenotype unresolved
  7. 2016 Medium

    Clarified the assembly requirements of the RAB33B effector complex, showing ATG5 is needed for high-affinity nucleotide-dependent RAB33B binding to ATG5-ATG16L1.

    Evidence Pulldown, isothermal titration calorimetry, deletion and point mutagenesis of ATG16L1

    PMID:26975471

    Open questions at the time
    • Single in vitro study
    • Cellular consequences of the assembly hierarchy not tested
  8. 2020 High

    Provided the structural mechanism: ATG16L1 is a noncanonical RAB-binding protein that activates RAB33B without nucleotide exchange and reciprocally controls phagophore localization.

    Evidence X-ray crystallography, FRET/FLIM, MST, Co-IP, LC3 lipidation, CLEM, starvation-induced autophagy assays, mutagenesis

    PMID:32960676

    Open questions at the time
    • Trigger for starvation-induced Golgi-to-phagophore translocation not fully defined
    • Coordination with the Golgi trafficking role unclear
  9. 2022 Medium

    Extended RAB33B function to cell migration via post-Golgi integrin delivery through the exocyst.

    Evidence siRNA migration screen, Co-IP with Exoc6, integrin trafficking and focal adhesion dynamics imaging

    PMID:35521520

    Open questions at the time
    • Whether this requires GTP cycling or specific GAPs/GEFs untested
    • Single lab finding
  10. 2023 Medium

    Demonstrated in vivo physiological consequences of a disease variant, linking RAB33B to osteoclast function and Golgi glycosylation.

    Evidence Knock-in mouse model, bone histomorphometry, biomechanical testing, lectin staining

    PMID:37359363

    Open questions at the time
    • Biochemical mechanism connecting RAB33B to glycosylation not dissected
    • Link to skeletal phenotype mechanistically incomplete
  11. 2025 Medium

    Refined the autophagy mechanism by identifying a LIR motif (GATE16-specific) and confirmed that disease variants destabilize RAB33B and impair autophagosome formation.

    Evidence Co-IP, LIR and disease-variant mutagenesis, autophagy induction assays, localization and stability analyses; plus viral co-option studies (HBV, IAV)

    PMID:40598642 PMID:40855209 PMID:41506134

    Open questions at the time
    • Interplay between LIR-GATE16 and ATG16L1 binding in phagophore recruitment unresolved
    • Single-lab findings for individual reports

Open questions

Synthesis pass · forward-looking unresolved questions
  • How RAB33B partitions between its Golgi trafficking, autophagy, and migration roles, and how a single GTPase is spatiotemporally directed among competing effectors and GAPs, remains unresolved.
  • No integrated model of effector/GAP selection across contexts
  • Mechanism connecting GTPase defects to tissue-specific skeletal disease unresolved

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0003924 GTPase activity 3
Localization
GO:0005794 Golgi apparatus 3
Pathway
R-HSA-9612973 Autophagy 3 R-HSA-5653656 Vesicle-mediated transport 2 R-HSA-9609507 Protein localization 2
Partners
ATG16L1ATG5EXOC6GATE16GM130OATL1RUTBC1

Evidence

Reading pass · 18 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 RAB33B localizes to the medial Golgi cisternae, as determined by immunofluorescence co-localization with alpha-mannosidase II and immunoelectron microscopy, suggesting a role in intra-Golgi transport. Immunofluorescence co-localization, immunoelectron microscopy Journal of cell science High 9512502
2001 RAB33B-GTP interacts with Golgi protein GM130 and endocytic rab effectors rabaptin-5 and rabex-5 (but not EEA1), and GTP-locked Rab33b inhibits anterograde intra-Golgi transport and retrograde glycosyltransferase recycling from Golgi to ER upon microinjection. Microinjection of GTPase-deficient mutants; GST pulldown with Western blot and mass spectrometry identification of binding partners FEBS letters Medium 11718716
2008 RAB33B (and RAB33A) specifically interacts with ATG16L in a GTP-dependent manner; expression of GTPase-deficient RAB33B-Q92L induces LC3 lipidation under nutrient-rich conditions and attenuates macroautophagy (p62 degradation); overexpression of the RAB33B-binding domain of ATG16L suppresses autophagosome formation, indicating RAB33B modulates autophagosome formation through ATG16L. Co-immunoprecipitation, GTPase-deficient mutant overexpression, LC3 lipidation assay, p62 degradation assay, dominant-negative domain overexpression Molecular biology of the cell High 18448665
2010 RAB33B acts downstream of trans-Golgi RAB6 in an intra-Golgi retrograde trafficking cascade: RAB33B knockdown suppresses COG- or ZW10-depletion-induced Golgi ribbon disruption; GTP-Rab6-induced relocation of Golgi enzymes to ER is RAB33B-dependent (but not vice versa); GTP-RAB33B overexpression dissociates RAB6 from Golgi membranes; RAB33B is required for Shiga-like toxin B fragment transport from trans to cis Golgi and ER. siRNA knockdown, GTP-restricted mutant overexpression, immunofluorescence of Golgi enzyme distribution, Shiga toxin transport assay Traffic (Copenhagen, Denmark) High 20163571
2011 OATL1 (a putative Rab-GAP) is a GAP for RAB33B and is recruited to autophagosomes via direct interaction with ATG8 homologues; RAB33B is involved in fusion between autophagosomes and lysosomes, and both OATL1's GAP activity and its ATG8-binding activity are required for this function, suggesting OATL1 uses ATG8 as a scaffold to inactivate RAB33B and regulate autophagosomal maturation. Co-immunoprecipitation, GAP activity assay, knockdown of OATL1 and RAB33B, autophagosome-lysosome fusion assay The Journal of cell biology High 21383079
2011 RUTBC1 is a GAP that activates GTP hydrolysis by RAB33B (and RAB32) in vitro, requiring Arg-803 of RUTBC1 in a dual-finger mechanism; RUTBC1 binds RAB9A-GTP but is not a GAP for RAB9A; RUTBC1 did not influence RAB33B binding to its effector ATG16L1 in cells. In vitro GAP activity assay, mutagenesis (Arg-803), Co-IP with RAB9A-GTP, effector-binding assay in cells The Journal of biological chemistry High 21808068
2012 The Ric1-Rgp1 complex (GEF for RAB6A) contains a distinct RAB33B-GTP binding site on the C terminus of Ric1, demonstrating that RAB33B-GTP recruits the Ric1-Rgp1 GEF to support a Rab cascade from medial (RAB33B) to trans (RAB6) Golgi. Pulldown/binding assay showing Ric1 C-terminus binds RAB33B-GTP; GEF activity assay for Rab6A; loss-of-function analysis (Ric1/Rgp1 depletion) The Journal of biological chemistry High 23091056
2012 A missense mutation in RAB33B replacing the invariant lysine in the guanine nucleotide-binding domain causes marked RAB33B protein deficiency (shown by Western blot and immunofluorescence), linking RAB33B dysfunction to Dyggve-Melchior-Clausen/Smith-McCort dysplasia. Exome sequencing, autozygosity mapping, Western blot, immunofluorescence Journal of medical genetics Medium 22652534
2015 RAB33B is required for hepatitis B virus naked capsid formation and release; RAB33B acts together with its effector complex ATG5-ATG12-ATG16L1 for proper capsid assembly and/or stability; capsid protein interacts with ATG5 and co-localizes with ATG5/12/16L1; a complete canonical autophagy pathway (including ATG8/LC3) is dispensable for this process. RNA interference knockdown, overexpression studies, co-immunoprecipitation, immunofluorescence co-localization, pharmacological autophagy inhibition Cellular microbiology Medium 25439980
2016 ATG5 is prerequisite for augmented nucleotide-dependent interaction of RAB33B with the dimeric ATG5-ATG16L1 complex; Arg-24 of ATG16L1 is crucial for its interaction with ATG5, which in turn affects RAB33B binding to the complex. Pulldown assay, isothermal titration calorimetry (ITC), deletion/point mutagenesis of ATG16L1 Biochemical and biophysical research communications Medium 26975471
2017 ACBD3 recruits TBC1D22 (a RAB33B-GAP) to a large multi-protein complex containing Golgin45 and GRASP55 at the medial Golgi, with ACBD3 binding Golgin45 via its GOLD domain, suggesting ACBD3 scaffolds Golgi stacking proteins together with a RAB33B-GAP. Proteomics (mass spectrometry), co-immunoprecipitation, overexpression/localization studies FEBS letters Medium 28777890
2017 RAB33B is required for HBV propagation: its knockdown reduces virus yield and inhibits nucleocapsid formation/trafficking; GDP-restricted RAB33B mutant phenocopies knockdown; RAB33B inactivation reduces core protein membrane association, implicating RAB33B in guiding core transport to nucleocapsid assembly sites and/or budding sites. RNAi knockdown, dominant-negative mutant overexpression, biochemical fractionation, immunofluorescence Viruses Medium 28635671
2020 Crystal structures of RAB33B bound to the coiled-coil domain (CCD) of ATG16L1 revealed that ATG16L1 is a noncanonical RAB-binding protein (RBP) that can induce RAB33B to adopt an active conformation without nucleotide exchange; RAB33B and ATG16L1 mutually determine each other's localization on phagophores; RAB33B-ATG16L1 interaction is required for LC3 lipidation and autophagosome formation; upon starvation, RAB33B translocates from Golgi to phagophores to recruit the ATG12-ATG5-ATG16L1 complex. X-ray crystallography, FRET/FLIM, microscale thermophoresis (MST), Co-IP, LC3 lipidation assay, correlative light and electron microscopy (CLEM), starvation-induced autophagy assay, mutagenesis Autophagy High 32960676
2022 RAB33B mediates post-Golgi transport to the plasma membrane and regulates cell migration by interacting with Exoc6 (a subunit of the exocyst complex) to deliver integrins to focal adhesions, thereby modulating focal adhesion dynamics and turnover. siRNA screen for cell migration, Co-immunoprecipitation of RAB33B with Exoc6, integrin trafficking assay, focal adhesion dynamics imaging iScience Medium 35521520
2023 A disease-causing Rab33b missense variant (K46Q) in mice causes bone resorption defects with increased osteoclast parameters and altered protein glycosylation patterns in cells and tissues, suggesting RAB33B has a role in osteoclast function and protein glycosylation at the Golgi. Knock-in mouse model, bone histomorphometry, biomechanical testing, lectin staining for protein glycosylation Frontiers in genetics Medium 37359363
2025 RAB33B contains a functional LIR (LC3-interacting region) motif that specifically mediates interaction with GATE16 (but not LC3B or other ATG8s); disrupting this LIR motif inhibits autophagy; upon autophagy induction, RAB33B is recruited from Golgi to phagophores in an LIR-dependent manner, enhancing interaction with TRPML3 to promote autophagosome formation. Co-immunoprecipitation, LIR mutant analysis, autophagy induction assays, fluorescence microscopy of RAB33B translocation Scientific reports Medium 40855209
2025 Five disease-causing RAB33B variants (two truncations, three missense) all show subcellular mislocalization away from Golgi membranes, are unstable and subject to premature degradation in cells; single amino acid substitution variants, when overexpressed during induced autophagy, cause severe reduction in LC3B-positive autophagosome number. Ectopic expression of mutant variants, immunofluorescence localization, Western blot for protein stability, LC3B puncta quantification during induced autophagy European journal of cell biology Medium 41506134
2025 RAB33B is upregulated by influenza A virus M2 protein and facilitates IAV replication by enhancing autophagy; RAB33B interacts with IAV M2 and LC3, mediating M2 membrane trafficking through autophagic-like vesicles; ATG16L1 (RAB33B effector) and TBC1D25 (RAB33B-GAP) contribute to IAV M2-induced autophagy. Transcriptional profiling of M2-overexpressing cells, Co-immunoprecipitation of RAB33B with M2 and LC3, autophagy flux assays, siRNA knockdown of RAB33B/ATG16L1/TBC1D25 Veterinary research Medium 40598642

Source papers

Stage 0 corpus · 24 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2008 Golgi-resident small GTPase Rab33B interacts with Atg16L and modulates autophagosome formation. Molecular biology of the cell 229 18448665
2011 OATL1, a novel autophagosome-resident Rab33B-GAP, regulates autophagosomal maturation. The Journal of cell biology 138 21383079
2001 Identification of rabaptin-5, rabex-5, and GM130 as putative effectors of rab33b, a regulator of retrograde traffic between the Golgi apparatus and ER. FEBS letters 102 11718716
2010 Rab33b and Rab6 are functionally overlapping regulators of Golgi homeostasis and trafficking. Traffic (Copenhagen, Denmark) 72 20163571
1998 A novel Rab GTPase, Rab33B, is ubiquitously expressed and localized to the medial Golgi cisternae. Journal of cell science 65 9512502
2012 Ric1-Rgp1 complex is a guanine nucleotide exchange factor for the late Golgi Rab6A GTPase and an effector of the medial Golgi Rab33B GTPase. The Journal of biological chemistry 63 23091056
2011 RUTBC1 protein, a Rab9A effector that activates GTP hydrolysis by Rab32 and Rab33B proteins. The Journal of biological chemistry 53 21808068
2015 Rab33B and its autophagic Atg5/12/16L1 effector assist in hepatitis B virus naked capsid formation and release. Cellular microbiology 38 25439980
2019 Multitasking Rab Proteins in Autophagy and Membrane Trafficking: A Focus on Rab33b. International journal of molecular sciences 37 31408960
2012 Mutation in RAB33B, which encodes a regulator of retrograde Golgi transport, defines a second Dyggve--Melchior--Clausen locus. Journal of medical genetics 33 22652534
2020 RAB33B recruits the ATG16L1 complex to the phagophore via a noncanonical RAB binding protein. Autophagy 32 32960676
2012 A novel RAB33B mutation in Smith-McCort dysplasia. Human mutation 32 23042644
2016 A systematic High-Content Screening microscopy approach reveals key roles for Rab33b, OATL1 and Myo6 in nanoparticle trafficking in HeLa cells. Scientific reports 20 27374232
2017 ACBD3 functions as a scaffold to organize the Golgi stacking proteins and a Rab33b-GAP. FEBS letters 19 28777890
2017 Rab33B Controls Hepatitis B Virus Assembly by Regulating Core Membrane Association and Nucleocapsid Processing. Viruses 16 28635671
2017 Additional three patients with Smith-McCort dysplasia due to novel RAB33B mutations. American journal of medical genetics. Part A 15 28127940
2022 Rab33b-exocyst interaction mediates localized secretion for focal adhesion turnover and cell migration. iScience 7 35521520
2016 Deciphering the role of Atg5 in nucleotide dependent interaction of Rab33B with the dimeric complex, Atg5-Atg16L1. Biochemical and biophysical research communications 6 26975471
2010 Proteomic approach with LCMS-IT-TOF identified an increase of Rab33B after transient focal cerebral ischemia in mice. Experimental & translational stroke medicine 6 21092243
2021 RAB33B and PCNT variants in two Pakistani families with skeletal dysplasia and short stature. BMC musculoskeletal disorders 5 34284742
2023 A Rab33b missense mouse model for Smith-McCort dysplasia shows bone resorption defects and altered protein glycosylation. Frontiers in genetics 1 37359363
2025 Host cellular protein RAB33B facilitates influenza viral replication and modulates M2 trafficking by enhancing autophagy. Veterinary research 0 40598642
2025 Two specific interactions of GATE16 with TRPML3 and RAB33B regulate autophagy. Scientific reports 0 40855209
2025 Mutations in the Rab33b protein that lead to the skeletal disease Smith-McCort dysplasia result in unstable proteins and altered autophagy function. European journal of cell biology 0 41506134

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