XPO6

XPO6 (Exportin-6) is a RAN-dependent nuclear export receptor that controls nuclear levels of actin and the actin-binding protein profilin-1, thereby coupling cytoskeletal monomer trafficking to transcriptional programs governing cell growth and adhesion (PMID:31414556, PMID:33596420). Its export activity is set by upstream regulators: laminin-111 signaling attenuates the PI3K pathway to upregulate XPO6-mediated nuclear actin efflux and impose epithelial quiescence (PMID:28591581), while RASSF1A localizes to the nuclear envelope and is required for XPO6 to engage RAN GTPase, sustaining nuclear actin export that supports MRTF-A/SRF transcriptional activity and proper cell adhesion (PMID:31414556). By exporting profilin-1, XPO6 limits nuclear profilin-1 available to bind the ENL subunit of the super elongation complex (SEC); loss of XPO6 accumulates nuclear profilin-1, which inhibits SEC-driven transcription of pro-cancer genes including MYC (PMID:33596420). XPO6-dependent depletion of nuclear actin monomers also opposes cAMP-induced proteasomal degradation of NF-κB RelA/p65, linking its transport activity to inflammatory signaling stability (PMID:35563720). Beyond its canonical actin/profilin cargo, XPO6 is required for nuclear release of HSV-1 glycoprotein M toward the trans-Golgi network during late infection (PMID:32817212).

1. 2017 Medium

   Established that XPO6-mediated nuclear actin export is an actively regulated node in growth control, placing it downstream of an extracellular matrix/PI3K signal rather than acting constitutively.

   Evidence siRNA knockdown, FRAP nuclear-actin dynamics, and PI3K inhibition in mammary epithelial cells

   PMID:28591581

   Open questions at the time

   • Does not define how PI3K signaling biochemically alters XPO6 activity
   • Single cell-type model (mammary epithelium)
2. 2019 High

   Identified RASSF1A as a required cofactor for XPO6–RAN engagement, explaining how nuclear actin export is licensed and linking its loss to MRTF-A/SRF deregulation and adhesion defects in cancer.

   Evidence Endogenous reciprocal Co-IP of RASSF1A–XPO6–RAN, fractionation/IF, knockdown with MRTF-A reporter and adhesion assays

   PMID:31414556

   Open questions at the time

   • Structural basis of how RASSF1A promotes XPO6–RAN binding not resolved
   • Whether RASSF1A regulates profilin-1 export equally is untested
3. 2019 Low

   Extended the regulatory model by implicating the Hippo kinase MST2 in controlling XPO6–RAN association alongside RASSF1A.

   Evidence Commentary inferring from primary data of PMID:31414556

   PMID:31528703

   Open questions at the time

   • Commentary with no independent experimental data
   • MST2's direct biochemical contribution to XPO6–RAN binding undefined
4. 2020 Medium

   Revealed a non-canonical cargo by showing XPO6 is required for nuclear release of HSV-1 glycoprotein M, expanding its role beyond actin/profilin to viral protein egress.

   Evidence BioID proximity proteomics for gM partners plus siRNA validation and IF localization tracking

   PMID:32817212

   Open questions at the time

   • Direct XPO6–gM binding and RAN-dependence not demonstrated
   • Single lab; novel cargo not independently replicated
5. 2021 High

   Provided the transcriptional consequence of profilin-1 export: nuclear profilin-1 retained upon XPO6 loss binds SEC component ENL and suppresses SEC-driven oncogenic transcription including MYC.

   Evidence XPO6 KD/overexpression in breast cancer cells, profilin-1/ENL Co-IP, reporter, ChIP-seq, rescue

   PMID:33596420

   Open questions at the time

   • Whether nuclear actin and nuclear profilin-1 act independently on SEC not separated
   • Stoichiometry of profilin-1–ENL inhibition unknown
6. 2022 Medium

   Connected XPO6-controlled nuclear actin levels to NF-κB stability, showing actin export opposes cAMP-induced proteasomal degradation of RelA/p65.

   Evidence XPO6 overexpression in forskolin-stimulated cells, NF-κB reporter, RelA/p65 half-life, MG132 rescue, ubiquitin pull-down

   PMID:35563720

   Open questions at the time

   • XPO6 used as a tool to lower nuclear actin rather than primary subject
   • Mechanism linking nuclear actin to RelA/p65 ubiquitination not defined
7. 2023 Low

   Reported that XPO6 promotes YAP1 expression and nuclear translocation to drive prostate cancer proliferation, migration and drug resistance.

   Evidence XPO6 KD/overexpression in PCa lines, YAP1 translocation assays, YAP1 inhibitor rescue, xenografts

   PMID:37243787

   Open questions at the time

   • Mechanistic link between an exportin and YAP1 nuclear import not biochemically explained
   • Single-lab, single approach for translocation
8. 2024 Medium

   Demonstrated a non-canonical mRNA-export role, with XPO6 facilitating nuclear export of TLR2 mRNA to amplify MyD88/NF-κB inflammatory signaling in COPD monocytes.

   Evidence XPO6 KD/overexpression, TLR2 mRNA nuclear export assay, cytokine ELISA, NF-κB reporter in mouse model and human samples

   PMID:38788453

   Open questions at the time

   • Direct XPO6–TLR2 mRNA association mechanism not shown
   • mRNA export is non-canonical for XPO6 and not independently confirmed
9. 2025 Low

   Placed XPO6 under post-transcriptional control by miR-3613-5p, with its downregulation promoting lung cancer aggressiveness.

   Evidence Dual-luciferase 3′UTR reporter, qRT-PCR, CCK-8, Transwell, rescue experiments

   PMID:41379264

   Open questions at the time

   • Provides no insight into XPO6 protein function beyond being a downstream effector
   • Single-lab validation

• How XPO6 distinguishes and engages its diverse cargoes (actin, profilin-1, viral gM, specific mRNAs) at the structural and RAN-dependent level remains unresolved.
• No structural model of XPO6–cargo recognition
• Whether non-canonical cargoes share the RAN-dependent mechanism is untested
• Cargo-selection determinants unknown