RAB43

RAB43 is a Golgi-localized Rab GTPase that organizes pre-Golgi and trans-Golgi membrane compartments and selectively sorts specific cargo through the secretory pathway (PMID:17684057, PMID:27899443, PMID:27053659). It maintains functional Golgi architecture: its depletion fragments and disperses the trans-Golgi network, and the GTPase-activating protein RN-tre (USP6NL) inactivates RAB43 and controls retrograde endosome-to-Golgi transport (PMID:17684057, PMID:21680502). A crystal structure of the RN-tre–RAB43 complex defines a bipartite recognition mechanism in which the GAP N-terminal subdomain catalytically remodels the RAB43 Switch regions while the C-terminal subdomain engages Switch II to confer substrate specificity, and disease-associated RN-tre mutations that impair this GAP activity produce aberrant Golgi architecture (PMID:41401861). Functionally, RAB43 acts as a cargo-selective trafficking factor: it routes a subset of membrane proteins through the medial Golgi (PMID:27053659) and drives anterograde ER-to-Golgi transport of nascent GPCRs through direct, activation-dependent receptor binding, a binding domain sufficient to confer RAB43-dependent transport on non-GPCR proteins (PMID:29069590). This sorting activity extends to specialized cell types: RAB43 governs dendritic and postsynaptic targeting of α2-adrenergic and muscarinic receptors in neurons via direct interaction (PMID:33676895), is required for cross-presentation of cell-associated antigens by CD8α+ dendritic cells (PMID:27899443), mediates anterograde surface transport of CD91 (LRP1) to support macrophage efferocytosis (PMID:35392093), and restrains TLR4–MyD88–MAPK–NF-κB inflammatory signaling by promoting ubiquitination and degradation of MyD88 in macrophages (PMID:41501355).

1. 2007 High

   Identifying the GAP for RAB43 established that the protein is a bona fide cycling Rab and placed it as a regulator of retrograde traffic into the Golgi and of Golgi integrity.

   Evidence Overexpression screen of 38 human Rab GAPs with Golgi morphology and protein transport readouts, identifying RN-tre (USP6NL) as the RAB43-specific GAP

   PMID:17684057

   Open questions at the time

   • Did not define the cargo RAB43 transports
   • Did not identify effectors downstream of active RAB43
2. 2008 Medium

   Dominant-negative and overexpression phenotypes localized RAB43 function to the pre-Golgi/ER-exit-site interface and linked it to microtubule-based positioning of Golgi intermediates.

   Evidence GFP-RAB43 dominant-negative (T32N) and overexpression with live-cell imaging, VSVG-GFP trafficking, and dynactin p150(Glued) co-localization

   PMID:18664496

   Open questions at the time

   • Mechanism connecting RAB43 to dynactin not resolved
   • Single lab; no direct effector identified
3. 2011 Medium

   Showed that RAB43-dependent TGN integrity is functionally required, using HSV-1 secondary envelopment as a sensitive readout of intact trans-Golgi membranes.

   Evidence Rab GAP overexpression screen plus RAB43 siRNA with electron microscopy and virion assembly/titer assays

   PMID:21680502

   Open questions at the time

   • Did not establish whether the defect reflects loss of a direct RAB43 cargo or general Golgi disruption
4. 2016 High

   Two studies converged on RAB43 as a cargo-selective sorter — through the medial Golgi for a subset of membrane proteins and as a requirement for dendritic-cell cross-presentation — moving beyond a purely structural role.

   Evidence GFP-RAB43 overexpression/siRNA with glycosylation and surface-delivery cargo assays; germline and conditional Rab43 knockout mice with cross-presentation assays and antibody localization

   PMID:27053659 PMID:27899443

   Open questions at the time

   • Molecular basis of cargo selectivity not yet defined
   • Identity of the cross-presentation cargo/compartment not pinned down
5. 2017 High

   Demonstrated direct, activation-dependent RAB43–GPCR binding and that the receptor RAB43-binding domain is transferable, explaining how RAB43 achieves cargo specificity in anterograde ER-to-Golgi transport.

   Evidence Rab siRNA screen for GPCR surface transport, dominant-negative/constitutively-active mutants, Co-IP with multiple GPCRs, and domain-swap chimeras

   PMID:29069590

   Open questions at the time

   • Structural basis of RAB43–receptor recognition not determined
   • Effector machinery linking bound cargo to vesicle movement unknown
6. 2021 High

   Extended the direct-interaction sorting model to neurons, showing RAB43 controls subtype-specific dendritic and postsynaptic receptor targeting and signaling.

   Evidence Dominant-negative and CRISPR-Cas9 Rab43 KO in primary neurons with Co-IP, postsynaptic imaging, and signaling assays for α2B-AR and M3 mAChR

   PMID:33676895

   Open questions at the time

   • How RAB43 distinguishes dendritic vs somatic routing not resolved
7. 2022 Medium

   Identified CD91/LRP1 as a RAB43 cargo in macrophages and connected RAB43 expression control to efferocytosis, linking the trafficking activity to a tissue function.

   Evidence Co-IP of RAB43 with CD91, knockdown/overexpression surface-localization assays, and Rab43 KO mice in an acute lung injury model

   PMID:35392093

   Open questions at the time

   • Mechanism by which HMGB1 suppresses RAB43 expression not detailed
   • Single lab
8. 2025 High

   A crystal structure of the RN-tre–RAB43 complex resolved the bipartite mechanism of GAP specificity and tied disease-associated RN-tre mutations to defective RAB43 inactivation and Golgi/endocytic phenotypes.

   Evidence X-ray crystallography of the RN-tre–RAB43 complex with mutational analysis, in vitro GAP assays, and Golgi morphology assays of disease mutants

   PMID:41401861

   Open questions at the time

   • No structure of active RAB43 bound to an effector or cargo
   • GEF for RAB43 not identified
9. 2025 Low

   An in vitro kinase screen nominated LRRK1 as a kinase phosphorylating RAB43 at Switch II, raising the possibility of kinase-regulated RAB43 cycling.

   Evidence In vitro kinase profiling of LRRK1, LRRK2, DYRK1A, MST1, and TBK1 against a Rab GTPase panel (preprint)

   PMID:bio_10.1101_2025.04.09.647999

   Open questions at the time

   • No cellular validation of LRRK1:RAB43 phosphorylation
   • Functional consequence of Switch-II phosphorylation unknown
   • Preprint, not peer-reviewed
10. 2026 Medium

    Revealed a signaling-regulatory role: RAB43 promotes MyD88 ubiquitination and degradation to dampen TLR4–MyD88–MAPK–NF-κB inflammatory output in macrophages.

    Evidence Myeloid-specific Rab43 KO mice in an LPS-induced ALI model with Co-IP of MyD88–ubiquitin, Western blot, qPCR of deubiquitinase genes, and flow cytometry

    PMID:41501355

    Open questions at the time

    • Whether RAB43 acts directly on MyD88 ubiquitination or via its trafficking activity is unresolved
    • Mechanism linking RAB43 to ubiquitinase gene expression (A20, SPOP, HOIL-1, OTUD4) unknown

• The activating GEF, the downstream effectors that link cargo-bound RAB43 to vesicle budding/movement, and whether Switch-II phosphorylation regulates RAB43 cycling in cells remain undefined.
• No GEF identified for RAB43
• No effector bridging RAB43 to motor/coat machinery characterized
• Cellular role of LRRK1-mediated phosphorylation not established