RPL38

RPL38 (eL38) is a small lysine-rich protein component of the large (60S) ribosomal subunit that, beyond contributing to general ribosome function, mediates selective translational control of specific mRNA subsets (PMID:621213, PMID:33926116). It was first isolated biochemically as a 60S subunit protein of ~8 kDa from rat liver ribosomes (PMID:621213). Genetic loss-of-function studies establish that RPL38 dosage is critical for development: in the Tail-short mouse, an Rpl38 deletion causes skeletal defects and conductive hearing loss that are rescued by an Rpl38 cDNA transgene, identifying Rpl38 deficiency as the causative lesion (PMID:21062742), and in Drosophila, RpL38 haploinsufficiency produces Minute phenotypes and altered organ growth via translational regulation (PMID:15520262). The selectivity of its translational role is shown by ribosome profiling in human cells, where RPL38 depletion preferentially reduces translation of transcriptional regulators including Hox genes while enhancing translation of basic metabolic genes, and concomitantly reorganizes transcription of ~1500 genes (PMID:33926116, PMID:33675855). In Drosophila spermatogonia, RpL38 is required for the transition to spermatocytes by sustaining expression of bag of marbles (bam), whose overexpression fully rescues the differentiation and fertility defects (PMID:39187660). Outside its ribosomal function, RPL38 directly interacts with the m6A methyltransferase METTL3 to promote m6A modification and suppression of SOCS2 mRNA, thereby modulating JAK2/STAT3 proinflammatory signaling and chondrocyte apoptosis in osteoarthritis (PMID:35596790).

1. 1978 High

   Established the physical identity of RPL38 as a discrete protein subunit of the large ribosomal particle, the foundational fact for all downstream functional work.

   Evidence Protein purification and biochemical characterization (ion exchange, gel filtration, SDS-PAGE, amino acid composition) of rat liver 60S ribosomes

   PMID:621213

   Open questions at the time

   • No structural placement within the 60S subunit
   • No functional role assigned beyond presence in the particle
2. 1991 Medium

   Defined the primary sequence and transcript of RPL38, confirming it as a small ~8 kDa protein and resolving its coding capacity.

   Evidence cDNA sequencing and Northern/Southern blotting of rat RPL38

   PMID:1840484

   Open questions at the time

   • Gene copy number estimate (11-13) confounded by pseudogenes not resolved
   • No functional assay of the encoded protein
3. 2004 Medium

   Showed via genetic loss-of-function that RpL38 dosage controls translational regulation of organ growth, establishing a developmental role beyond housekeeping ribosome assembly.

   Evidence Genetic screen and heterozygous mutant phenotypic analysis (Minute phenotype, increased cell size) in Drosophila

   PMID:15520262

   Open questions at the time

   • Specific mRNA targets of altered translation not identified
   • Mechanism linking RpL38 dosage to cell size unknown
4. 2010 High

   Demonstrated by transgenic rescue that Rpl38 deficiency is causative for axial skeletal defects and conductive hearing loss in the Tail-short mouse, linking a ribosomal protein to tissue-specific developmental phenotypes.

   Evidence Genetic mapping, deletion characterization, transgenic rescue, and auditory/immunohistochemical assays in mouse

   PMID:21062742

   Open questions at the time

   • Molecular basis of tissue-specific phenotype from a general ribosomal protein not resolved
   • Target mRNAs driving the phenotype not defined in this study
5. 2021 Medium

   Provided genome-wide evidence that RPL38 mediates selective translational control, preferentially affecting transcriptional regulators including Hox genes, and that its loss reorganizes the transcriptome.

   Evidence siRNA knockdown with ribosome profiling and RNA-seq in HEK293 cells

   PMID:33675855 PMID:33926116

   Open questions at the time

   • Whether translational effects are direct or secondary to ribosome biogenesis stress not separated
   • Single cell line, single lab
   • Mechanism of mRNA selectivity not established
6. 2022 Medium

   Revealed a non-ribosomal moonlighting function: RPL38 partners with METTL3 to promote m6A-dependent suppression of SOCS2, coupling it to JAK2/STAT3 inflammatory signaling in chondrocytes.

   Evidence Co-IP, m6A analysis, JAK2/STAT3 pathway assays, and in vivo mouse osteoarthritis model with siRNA knockdown

   PMID:35596790

   Open questions at the time

   • Whether the RPL38-METTL3 interaction is direct or ribosome-mediated not resolved
   • Single lab
   • Generality beyond chondrocytes unknown
7. 2024 High

   Established by genetic epistasis that RpL38 drives spermatogonial differentiation through downstream bam expression, pinpointing a specific effector of its tissue-specific role.

   Evidence RNAi knockdown, proteomics/transcriptomics, and bam overexpression rescue with fertility assays in Drosophila testis

   PMID:39187660

   Open questions at the time

   • Whether RpL38 controls bam at the level of translation versus transcription not fully resolved
   • Conservation of the RpL38-bam axis in mammals untested
8. 2025 Low

   Implicated the importin Kap121/Pse1 in RPL38 nuclear import, addressing how the protein traffics to the nucleus prior to ribosome assembly.

   Evidence TurboID proximity labeling proxiOME screen in S. cerevisiae (preprint)

   PMID:bio_10.1101_2025.09.18.677003

   Open questions at the time

   • Proximity labeling only, no Co-IP or structural validation
   • Preprint, single method, single lab
   • Functional consequence of disrupting the interaction not tested

• How a general 60S ribosomal protein achieves the mRNA selectivity that produces tissue-specific developmental phenotypes remains mechanistically unresolved.
• No structural basis for selective translation of Hox or other target mRNAs
• Relationship between ribosomal and METTL3-associated functions unclear
• Direct molecular determinants of target mRNA recognition unknown