bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2023‒09‒03
six papers selected by
Thomas Farid Martínez, University of California, Irvine

  1. Zhejiang Da Xue Xue Bao Yi Xue Ban. 2023 Aug 25. pii: 1008-9292(2023)04-0397-09. [Epub ahead of print]52(4): 397-405
      Long non-coding RNAs (lncRNAs) which are usually thought to have no protein coding ability, are widely involved in cell proliferation, signal transduction and other biological activities. However, recent studies have suggested that short open reading frames (sORFs) of some lncRNAs can encode small functional peptides (micropeptides). These micropeptides appear to play important roles in calcium homeostasis, embryonic development and tumorigenesis, suggesting their potential as therapeutic targets and diagnostic biomarkers. Currently, bioinformatic tools as well as experimental methods such as ribosome mapping and in vitro translation are applied to predict the coding potential of lncRNAs. Furthermore, mass spectrometry, specific antibodies and epitope tags are used for validating the expression of micropeptides. Here, we review the physiological and pathological functions of recently identified micropeptides as well as research strategies for predicting the coding potential of lncRNAs to facilitate the further research of lncRNA encoded micropeptides.
    Keywords:  Long non-coding RNA; Mass spectrometry; Micropeptide; Review; Ribosome profiling; Short open reading frame
  2. Biochem Biophys Res Commun. 2023 Aug 17. pii: S0006-291X(23)00979-8. [Epub ahead of print]678 115-121
      Loss of hair cells can lead to irreversible sensorineural hearing loss. Therefore, hair cell preservation is critical for hearing. Mitochondrial derived peptides (MDPs) are bioactive peptides and prominent members of this family are humanin (HN) and the mitochondrial-open-reading frame of the twelve S c (MOTS-c). The protective roles of HN and MOTS-c in age-related diseases and in various tissues exposed to cellular stresses have been demonstrated. The involvement of MDPs in the inner ear remains to be investigated. Therefore, we determined the expression of rattin, the homolog of humanin, in inner ear tissues. Then, we found that HN and MOTS-c showed a significant protective effect on hair cells in organ of Corti explants exposed to gentamicin. Treatment with HN decreased gentamicin-induced phosphorylation of AKT, whereas treatment with MOTS-c increased phosphorylation of AMPKα in explants. Our data indicate that MDPs exert a protective function in gentamicin-induced hair cell damage. Therefore, MDPs may contribute to design new preventive strategies against hearing loss.
    Keywords:  Cochlea; Gentamicin; Hair cells; Humanin; MOTS-C; Mitochondrial derived peptides
  3. Sci Rep. 2023 08 29. 13(1): 14110
      Mitochondrial-derived peptides are encoded by mitochondrial DNA but have biological activity outside mitochondria. Eight of these are encoded by sequences within the mitochondrial 12S and 16S ribosomal genes: humanin, MOTS-c, and the six SHLP peptides, SHLP1-SHLP6. These peptides have various effects in cell culture and animal models, affecting neuroprotection, insulin sensitivity, and apoptosis, and some are secreted, potentially having extracellular signaling roles. However, except for humanin, their importance in normal cell function is unknown. To gauge their importance, their coding sequences in vertebrates have been analyzed for synonymous codon bias. Because they lie in RNA genes, such bias should only occur if their amino acids have been conserved to maintain biological function. Humanin and SHLP6 show strong synonymous codon bias and sequence conservation. In contrast, SHLP1, SHLP2, SHLP3, and SHLP5 show no significant bias and are poorly conserved. MOTS-c and SHLP4 also lack significant bias, but contain highly conserved N-terminal regions, and their biological importance cannot be ruled out. An additional potential mitochondrial-derived peptide sequence was discovered preceding SHLP2, named SHLP2b, which also contains a highly conserved N-terminal region with synonymous codon bias.
  4. Cell Death Dis. 2023 08 26. 14(8): 568
      Sustained activation of DNA damage response (DDR) signaling has been demonstrated to play vital role in chemotherapy failure in cancer. However, the mechanism underlying DDR sustaining in cancer cells remains unclear. In the current study, we found that the expression of the DDUP microprotein, encoded by the CTBP1-DT lncRNA, drastically increased in cisplatin-resistant ovarian cancer cells and was inversely correlated to cisplatin-based therapy response. Using a patient-derived human cancer cell model, we observed that DNA damage-induced DDUP foci sustained the RAD18/RAD51C and RAD18/PCNA complexes at the sites of DNA damage, consequently resulting in cisplatin resistance through dual RAD51C-mediated homologous recombination (HR) and proliferating cell nuclear antigen (PCNA)-mediated post-replication repair (PRR) mechanisms. Notably, treatment with an ATR inhibitor disrupted the DDUP/RAD18 interaction and abolished the effect of DDUP on prolonged DNA damage signaling, which resulted in the hypersensitivity of ovarian cancer cells to cisplatin-based therapy in vivo. Altogether, our study provides insights into DDUP-mediated aberrant DDR signaling in cisplatin resistance and describes a potential novel therapeutic approach for the management of platinum-resistant ovarian cancer.
  5. Am J Physiol Cell Physiol. 2023 Aug 29.
      Mitochondria rely upon the coordination of protein import, protein translation, and proper functioning of oxidative phosphorylation (OXPHOS) complexes I-V to sustain the activities of life for an organism. Each process is dependent upon the function of profoundly large protein complexes found in the mitochondria (TOMM complex, TIMM complex, OXPHOS complexes, mitoribosomes). These massive protein complexes, in some instances more than one megadalton, are built up from numerous protein subunits of varying sizes, including many proteins that are ≤100-150 amino acids. However, these small proteins, termed microproteins, not only act as cogs in large molecular machines; they also have important steps in inhibiting or promoting the intrinsic pathway of apoptosis, coordinate responses to cellular stress and even act as hormones. This review focuses on microproteins that occupy the mitochondria and are critical for its function. Although the microprotein field is relatively new, researchers have long recognized the existence of these mitochondrial proteins as critical components of virtually all aspects of mitochondrial biology. Thus, recent studies estimating that hundreds of new microproteins of unknown function exist and are missing from current genome annotations suggests that the mitochondrial "microproteome" is a rich area for future biological investigation.
    Keywords:  cell stress; microproteins; mitochondria; mitochondrial protein import; oxidative phosphorylation
  6. Trends Plant Sci. 2023 Aug 26. pii: S1360-1385(23)00236-4. [Epub ahead of print]
      Taking advantage of natural variation promotes our understanding of phenotypic diversity and trait evolution, ultimately accelerating plant breeding, in which the identification of causal variations is critical. To date, sequence variations in the coding region and transcription level polymorphisms caused by variations in the promoter have been prioritized. An upstream open reading frame (uORF) in the 5' untranslated region (5' UTR) regulates gene expression at the post-transcription or translation level. In recent years, studies have demonstrated that natural uORF variations shape phenotypic diversity. This opinion article highlights recent researches and speculates on future directions for natural uORF variation in plants.
    Keywords:  natural variation; phenotypic diversity; translational regulation; uORF