bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2024–02–18
six papers selected by
Thomas Farid Martínez, University of California, Irvine
  1. Novel insights into small open reading frame-encoded micropeptides in hepatocellular carcinoma: A potential breakthrough.
  2. The lncRNA Malat1 is trafficked to the cytoplasm as a localized mRNA encoding a small peptide in neurons.
  3. An upstream open reading frame (5'-uORF) links oxidative stress to translational control of ALCAT1 through phosphorylation of eIF2α.
  4. A novel lncRNA-hidden polypeptide regulates malignant phenotypes and pemetrexed sensitivity in A549 pulmonary adenocarcinoma cells.
  5. Regulation of non-canonical proteins from diverse origins through the nonsense-mediated mRNA decay pathway.
  6. Ultrafast Biomimetic Oxidative Folding of Cysteine-rich Peptides and Microproteins in Organic Solvents.
  1. Cancer Lett. 2024 Feb 13. pii: S0304-3835(24)00084-3. [Epub ahead of print] 216691
    Novel insights into small open reading frame-encoded micropeptides in hepatocellular carcinoma: A potential breakthrough.
    Qiangnu Zhang, Liping Liu.
      Traditionally, non-coding RNAs (ncRNAs) are regarded as a class of RNA transcripts that lack encoding capability; however, advancements in technology have revealed that some ncRNAs contain small open reading frames (sORFs) that are capable of encoding micropeptides of approximately 150 amino acids in length. sORF-encoded micropeptides (SEPs) have emerged as intriguing entities in hepatocellular carcinoma (HCC) research, shedding light on this previously unexplored realm. Recent studies have highlighted the regulatory functions of SEPs in the occurrence and progression of HCC. Some SEPs exhibit inhibitory effects on HCC, but others facilitate its development. This discovery has revolutionized the landscape of HCC research and clinical management. Here, we introduce the concept and characteristics of SEPs, summarize their associations with HCC, and elucidate their carcinogenic mechanisms in HCC metabolism, signaling pathways, cell proliferation, and metastasis. In addition, we propose a step-by-step workflow for the investigation of HCC-associated SEPs. Lastly, we discuss the challenges and prospects of applying SEPs in the diagnosis and treatment of HCC. This review aims to facilitate the discovery, optimization, and clinical application of HCC-related SEPs, inspiring the development of early diagnostic, individualized, and precision therapeutic strategies for HCC.
    Keywords:  HCC; Micropeptides; SEPs; ncRNAs; sORFs
    DOI:  https://doi.org/10.1016/j.canlet.2024.216691
  2. bioRxiv. 2024 Feb 01. pii: 2024.02.01.578240. [Epub ahead of print]
    The lncRNA Malat1 is trafficked to the cytoplasm as a localized mRNA encoding a small peptide in neurons.
    Wen Xiao, Reem Halabi, Chia-Ho Lin, Mohammad Nazim, Kyu-Hyeon Yeom, Douglas L Black.
      Synaptic function is modulated by local translation of mRNAs that are transported to distal portions of axons and dendrites. The Metastasis-associated lung adenocarcinoma transcript 1 ( MALAT1 ) is broadly expressed across cell types, almost exclusively as a nuclear non-coding RNA. We found that in differentiating neurons, a portion of Malat1 RNA redistributes to the cytoplasm. Depletion of Malat1 from neurons stimulated expression of particular pre- and post-synaptic proteins, implicating Malat1 in their regulation. Neuronal Malat1 is localized to both axons and dendrites in puncta that co-stain with Staufen1 protein, similar to neuronal granules formed by locally translated mRNAs. Ribosome profiling of mouse cortical neurons identified ribosome footprints within a region of Malat1 containing short open reading frames. The upstream-most reading frame (M1) of the Malat1 locus was linked to the GFP coding sequence in mouse ES cells. When these gene-edited cells were differentiated into glutamatergic neurons, the M1-GFP fusion protein was expressed. Antibody staining for the M1 peptide confirmed its presence in wildtype neurons, and showed enhancement of M1 expression after synaptic stimulation with KCL. Our results indicate that Malat1 serves as a cytoplasmic coding RNA in the brain that is both modulated by and modulates synaptic function.
    DOI:  https://doi.org/10.1101/2024.02.01.578240
  3. Free Radic Biol Med. 2024 Feb 13. pii: S0891-5849(24)00097-2. [Epub ahead of print]
    An upstream open reading frame (5'-uORF) links oxidative stress to translational control of ALCAT1 through phosphorylation of eIF2α.
    Jun Zhang, Yuguang Shi.
      Acyl-CoA:lysocardiolipin acyltransferase 1 (ALCAT1) is an enzyme that promotes mitochondrial dysfunction by catalyzing pathological remodeling of cardiolipin. Upregulation of ALCAT1 protein expression by oxidative stress is implicated in the pathogenesis of age-related metabolic diseases, but the underlying molecular mechanisms remain elusive. In this study, we identified a highly conserved upstream open reading frame (uORF) at the 5'-untranslated region (5'-UTR) of ALCAT1 mRNA as a key regulator of ALCAT1 expression in response to oxidative stress. We show that the uORF serves as a decoy that prevents translation initiation of ALCAT1 under homeostatic condition. The inhibitory activity of the uORF on ALCAT1 mRNA translation is mitigated by oxidative stress but not ER stress, which requires the phosphorylation of eukaryotic translation initiation factor 2α (eIF2α). Consequently, ablation of uORF or eIF2α phosphorylation at Ser51 renders ALCAT1 protein expression unresponsive to induction by oxidative stress. Taken together, our data show that the uORF links oxidative stress to translation control of ALCAT1 mRNAs through phosphorylation of eIF2α at Ser51.
    Keywords:  5′UTR; ALCAT1; Oxidative stress; Translational control; eIF2α; uORF
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.02.015
  4. Amino Acids. 2024 Feb 13. 56(1): 15
    A novel lncRNA-hidden polypeptide regulates malignant phenotypes and pemetrexed sensitivity in A549 pulmonary adenocarcinoma cells.
    Xiaobing Han, Liangxin Chen, Peng Sun, Xiuqing Wang, Qian Zhao, Lingfeng Liao, Dejin Lou, Nan Zhou, Yujun Wang.
      The advance of high-throughput sequencing enhances the discovery of short ORFs embedded in long non-coding RNAs (lncRNAs). Here, we uncovered the production and biological activity of lncRNA-hidden polypeptides in lung adenocarcinoma (LUAD). In the present study, bioinformatics was used to screen the lncRNA-hidden polypeptides in LUAD. Analysis of protein expression was done by western blot or immunofluorescence assay. The functions of the polypeptide were determined by detecting its effects on cell viability, proliferation, migration, invasion, and pemetrexed (PEM) sensitivity. The protein interactors of the polypeptide were analyzed by mass spectrometry after Co-immunoprecipitation (Co-IP) assay. The results showed that the lncRNA LINC00954 was confirmed to encode a novel polypeptide LINC00954-ORF. The polypeptide had tumor-suppressor features in A549 cells by repressing cell growth, motility and invasion. Moreover, the polypeptide enhanced PEM sensitivity and suppressed growth in A549/PEM cells. The protein interactors of this polypeptide had close correlations with RNA processing, amide metabolic process, translation, RNA binding, RNA transport, and DNA replication. As a conclusion, the LINC00954-ORF polypeptide embedded in lncRNA LINC00954 possesses tumor-suppressor features in A549 and PEM-resistant A549 cells and sensitizes PEM-resistant A549 cells to PEM, providing evidence that the LINC00954-ORF polypeptide is a potential anti-cancer agent in LUAD.
    Keywords:  LINC00954-ORF; NSCLC; PEM resistance; Short ORFs; lncRNA-hidden polypeptides
    DOI:  https://doi.org/10.1007/s00726-023-03361-7
  5. Proteomics. 2024 Feb 13. e2300361
    Regulation of non-canonical proteins from diverse origins through the nonsense-mediated mRNA decay pathway.
    Parthiban Periasamy, Craig Joseph, Adrian Campos, Sureka Rajandran, Christopher Batho, James E Hudson, Haran Sivakumaran, Hitesh Kore, Keshava Datta, Joe Yeong, Harsha Gowda.
      Immunotherapy harnesses neoantigens encoded within the human genome, but their therapeutic potential is hampered by low expression, which may be controlled by the nonsense-mediated mRNA decay (NMD) pathway. This study investigates the impact of UPF1-knockdown on the expression of non-canonical/mutant proteins, employing proteogenomic to explore UPF1 role within the NMD pathway. Additionally, we conducted a comprehensive pan-cancer analysis of UPF1 expression and evaluated UPF1 expression in Triple-Negative Breast Cancer (TNBC) tissue in-vivo. Our findings reveal that UPF1-knockdown leads to increased translation of non-canonical/mutant proteins, particularly those originating from retained-introns, pseudogenes, long non-coding RNAs, and unannotated transcript biotypes. Moreover, our analysis demonstrates elevated UPF1 expression in various cancer types, with notably heightened protein levels in patient-derived TNBC tumors compared to adjacent tissues. This study elucidates UPF1 role in mitigating transcriptional noise by degrading transcripts encoding non-canonical/mutant proteins. Targeting this mechanism may reveal a new spectrum of neoantigens accessible to the antigen presentation pathway. Our novel findings provide a strong foundation for the development of therapeutic strategies aimed at targeting UPF1 or modulating the NMD pathway.
    Keywords:  UPF1; mutant protein; mutant transcript; nonsense-mediated decay pathway; transcriptional noise
    DOI:  https://doi.org/10.1002/pmic.202300361
  6. Angew Chem Int Ed Engl. 2024 Feb 11. e202317789
    Ultrafast Biomimetic Oxidative Folding of Cysteine-rich Peptides and Microproteins in Organic Solvents.
    Antony Kam, Shining Loo, Yibo Qiu, Chuan-Fa Liu, James P Tam.
      Disulfides in peptides and proteins are essential for maintaining a properly folded structure. Their oxidative folding is invariably performed in an aqueous-buffered solution. However, this process is often slow and can lead to misfolded products. Here, we report a novel concept and strategy that is bio-inspired to mimic protein disulfide isomerase (PDI) by accelerating disulfide exchange rates many thousand-fold. The proposed strategy termed organic oxidative folding is performed entirely under polar aprotic solvents to yield correctly folded microproteins instantaneously without observable misfolded or dead-end products. Compared to conventional aqueous oxidative folding strategies, enormously large rate accelerations up to 113,200-fold were observed. The feasibility and generality of the organic oxidative folding strategy was successfully demonstrated on 15 cysteine-rich microproteins of different hydrophobicity, lengths (14 to 58 residues), and numbers of disulfides (2 to 5 disulfides), producing the native products in a second and in high yield.
    Keywords:  cysteine-rich peptides; microproteins; organic solvents; oxidative folding; thiol-disulfide exchange
    DOI:  https://doi.org/10.1002/anie.202317789
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