NUP42

NUP42 (hCG1/Rip1p) is an FG-nucleoporin on the cytoplasmic face of the nuclear pore complex that serves as a scaffold anchoring the mRNA export factor Gle1/hGle1B at the NPC, where the Nup42 C-terminal domain, Gle1, and inositol hexakisphosphate cooperatively stimulate the DEAD-box ATPase Dbp5/DDX19B to remodel mRNPs during the terminal step of mRNA export (PMID:10610322, PMID:28869701). Nup42 forms a heterotrimeric complex with hNup155 and hGle1B, and its depletion causes cytoplasmic mislocalization of Gle1 and specifically impairs heat-shock-induced Hsp70 mRNA export and chaperone protein production (PMID:16000379). Independent of its mRNA export role, Nup42 promotes CRM1-dependent nuclear protein export by facilitating trimeric CRM1–RanGTP–NES-cargo complex formation through a mechanism that does not require its FG repeats (PMID:22250199). The N-terminal region of Nup42 also serves as a docking site for HIV-1 Vpr at the nuclear envelope (PMID:12228227).

1. 1999 High

   Establishing that Nup42/Rip1p physically links Gle1p and Dbp5p at the cytoplasmic face of the NPC answered how these mRNA export factors are recruited to the terminal export step, and cross-species complementation by human hCG1 demonstrated evolutionary conservation.

   Evidence Genetic suppressor screen, co-immunoprecipitation, immuno-EM, and yeast complementation in S. cerevisiae and human cells

   PMID:10610322

   Open questions at the time

   • Biochemical mechanism by which Nup42 potentiates Dbp5 ATPase activity was not determined
   • Direct binding interfaces on Nup42 for Gle1 versus Dbp5 were not mapped
   • Bulk versus transcript-specific mRNA export contribution was unclear
2. 2002 High

   Identification of hCG1/NUP42 as the nuclear envelope docking factor for HIV-1 Vpr revealed an unexpected viral exploitation of this nucleoporin, mapping the interaction to the N-terminal non-FG region.

   Evidence Yeast two-hybrid, in vitro binding, co-IP in transfected cells, and digitonin-permeabilized cell import assay

   PMID:12228227

   Open questions at the time

   • Whether Vpr docking through Nup42 contributes to viral nuclear import or NPC disruption was not resolved
   • Structural basis of the Vpr–hCG1 interaction was not determined
3. 2005 High

   Demonstrating that the hGle1B C-terminal tail binds the non-FG region of hCG1 and that their depletion blocks heat-shock Hsp70 mRNA export established that the yeast Nup42–Gle1 export axis is functionally conserved in human cells with transcript-selective consequences.

   Evidence In vitro reconstitution of hNup155–hGle1B–hCG1 heterotrimer, siRNA knockdown in HeLa cells, Hsp70 mRNA FISH, and immunoblot

   PMID:16000379

   Open questions at the time

   • Whether Nup42 loss affects bulk poly(A)+ mRNA export or only specific transcripts was not fully resolved
   • Role of hNup155 within the trimeric complex was not functionally dissected
4. 2012 High

   Discovery that NUP42/NLP1 promotes CRM1-dependent protein export independently of its FG repeats broadened Nup42 function beyond mRNA export and identified it as a facilitator of CRM1–RanGTP–NES-cargo complex assembly.

   Evidence Gain- and loss-of-function experiments (overexpression and siRNA), domain deletion mutagenesis, co-IP with CRM1 complexes, and nuclear export assays

   PMID:22250199

   Open questions at the time

   • Whether the mRNA export and CRM1-dependent protein export functions are mechanistically coupled or independent was not tested
   • Structural basis of CRM1 binding to the non-FG region of Nup42 was not defined
5. 2017 High

   Biochemical reconstitution of the Nup42-CTD/Gle1/Dbp5 trimeric complex with IP6 resolved the long-standing question of how Nup42 potentiates Gle1-mediated activation of Dbp5/DDX19B ATPase activity, showing Nup42 and IP6 act through a shared, non-additive mechanism conserved from yeast to humans.

   Evidence In vitro ATPase stimulation with recombinant proteins, co-IP, domain mutagenesis, yeast genetics, siRNA in human cells, and mRNA export assays across two species

   PMID:28869701

   Open questions at the time

   • Atomic-resolution structure of the full Nup42-CTD/Gle1/Dbp5/IP6 complex was not available
   • Whether Nup42-mediated Dbp5 activation is transcript-selective was not addressed
6. 2026 Medium

   A genome-wide CRISPRi screen identified Nup42 as the top suppressor of heat-induced mRNA condensation, revealing that beyond mRNA export, Nup42 safeguards co-transcriptional mRNP solubility of chaperone transcripts to enable their translation during heat shock. (preprint)

   Evidence CRISPRi screen (FRep-Seq), mRNA fractionation, live-cell imaging, translation assays, and transcription inhibition experiments (preprint)

   PMID:41727045

   Open questions at the time

   • Findings await peer review
   • Direct molecular mechanism by which Nup42 prevents mRNA condensation (e.g., through mRNP remodeling or chaperoning) is unknown
   • Whether this mRNP solubility function operates through the Gle1–Dbp5 axis or an independent pathway was not determined

• A unifying structural and mechanistic model explaining how Nup42 coordinates its dual roles in mRNA export (Gle1/Dbp5 activation), CRM1-dependent protein export, viral docking, and mRNP solubility control remains to be established.
• No high-resolution structure of full-length Nup42 in complex with its partners exists
• Whether the mRNA export, CRM1 export, and mRNP solubility functions compete for the same Nup42 pools or operate through distinct sub-complexes is unknown
• In vivo contribution of Nup42 to bulk versus heat-shock-specific mRNA export in mammalian tissues has not been assessed