RPLP2

RPLP2 is a ribosomal stalk protein that, together with RPLP0 and RPLP1, promotes translation elongation through challenging mRNA sequences, most notably those encoding multiple adjacent transmembrane domains where it relieves ribosome pausing during multi-pass membrane protein biogenesis (PMID:32890404). This elongation function makes RPLP1/2 essential host factors for the replication of flaviviruses (DENV, YFV, ZIKV), whose structural polyproteins are TMD-rich (PMID:27974556, PMID:32890404). RPLP2 also supports selective translation initiation of viral mRNAs: during coronavirus (PEDV) infection it is upregulated via phospho-eIF4E and engages the viral 5'UTR through association with eIF4E, recruiting the viral nucleocapsid protein into cap-bound complexes (PMID:36632964). Beyond its ribosomal role, RPLP2 has been implicated in cancer cell metabolism and survival, where it activates TLR4/PI3K/AKT signaling to drive HIF-1α-dependent aerobic glycolysis in hepatocellular carcinoma (PMID:38052785) and sustains expression of the ferroptosis suppressor frataxin in diffuse large B-cell lymphoma (PMID:40564039). RPLP2 mRNA is subject to METTL14-deposited m6A modification, read by YTHDC2, which destabilizes the transcript and suppresses RPLP2 expression in hepatocellular carcinoma (PMID:39955344).

1. 2017 High

   Established that the ribosomal stalk proteins RPLP1/2 are not merely structural but are selectively required host factors for flavivirus replication, linking them to viral protein synthesis.

   Evidence RNAi knockdown in A549 and HuH-7 cells with metabolic labeling and exogenous transgene reporter assays for DENV, YFV, ZIKV

   PMID:27974556

   Open questions at the time

   • Did not resolve the precise step of translation affected
   • Mechanism distinguishing viral from cellular mRNA dependence unclear at this stage
2. 2020 High

   Defined the molecular mechanism of RPLP1/2 action, showing they relieve ribosome pausing within sequences encoding multiple adjacent transmembrane domains, explaining both flaviviral dependence and a general role in multi-pass membrane protein biogenesis.

   Evidence Ribosome profiling in RPLP1/2-depleted cells plus DENV envelope protein stability and global translational analysis

   PMID:32890404

   Open questions at the time

   • Structural basis for how the stalk senses TMD-encoding sequences not determined
   • Whether RPLP2 acts independently of RPLP1 not resolved
3. 2023 Medium

   Extended RPLP2's pro-viral role to coronaviruses and to translation initiation, showing it bridges the viral 5'UTR and nucleocapsid protein to the cap-binding machinery via eIF4E.

   Evidence TMT proteomics, polysome profiling, RNA-binding protein immunoprecipitation and m7GTP cap pull-down during PEDV infection

   PMID:36632964

   Open questions at the time

   • Direct RPLP2–eIF4E binding interface not mapped
   • Single lab; initiation role contrasts with the elongation role established for flaviviruses
4. 2023 Medium

   Identified an extra-ribosomal function for RPLP2 in cancer metabolism, placing it upstream of TLR4/PI3K/AKT/HIF-1α signaling that drives aerobic glycolysis in hepatocellular carcinoma.

   Evidence siRNA knockdown with glycolytic enzyme/lactate readouts, PI3K/AKT inhibition and HIF-1α nuclear localization assays in HCC cells

   PMID:38052785

   Open questions at the time

   • Direct RPLP2–TLR4 interaction not validated by binding assay
   • How a ribosomal protein reaches the cell surface for autocrine signaling unexplained
5. 2025 Medium

   Showed RPLP2 expression is itself regulated post-transcriptionally, with METTL14-deposited m6A read by YTHDC2 destabilizing RPLP2 mRNA to suppress HCC progression.

   Evidence MeRIP, dual-luciferase reporter, RNA stability assays with METTL14 overexpression and RPLP2 knockdown in HCC cells

   PMID:39955344

   Open questions at the time

   • Site-specific m6A residues on RPLP2 mRNA not mapped
   • Single lab; relationship to the TLR4/glycolysis axis not integrated
6. 2025 Medium

   Linked RPLP2 to tumor cell survival via ferroptosis control, showing its depletion lowers frataxin and triggers ferroptosis in DLBCL.

   Evidence siRNA knockdown with lipid ROS/iron ferroptosis markers, proliferation assays and xenograft models in DLBCL

   PMID:40564039

   Open questions at the time

   • Molecular link between RPLP2 and FXN expression not elucidated
   • Whether this reflects ribosomal or extra-ribosomal RPLP2 function unknown
7. 2024 Low

   Proposed an upstream regulator of RPLP2 in autoimmune disease, with lncRNA DSCR9 negatively regulating RPLP2 to control PI3K/AKT-driven inflammation in rheumatoid arthritis fibroblasts.

   Evidence RNA pull-down, Western blot, EdU assay and PI3K/AKT agonist rescue in RA fibroblasts

   PMID:39376558

   Open questions at the time

   • Mechanistic link to PI3K/AKT rests largely on pathway inhibitor/agonist experiments rather than direct interaction
   • DSCR9–RPLP2 regulation not confirmed by orthogonal methods
   • Single lab

• How RPLP2's canonical ribosomal stalk function mechanistically connects to its reported extra-ribosomal signaling roles (TLR4 activation, ferroptosis regulation) remains unresolved.
• No structural or biochemical account of RPLP2 acting outside the ribosome
• Direct binding partners in the signaling roles not established