bims-micpro Biomed News
on Discovery and characterization of microproteins
Issue of 2021–10–03
seven papers selected by
Thomas Farid Martínez, University of California, Irvine
  1. Little but Loud. The Diversity of Functions of Small Proteins and Peptides - Translational Products of Short Reading Frames.
  2. Pegasus, a small extracellular peptide enhancing short-range diffusion of Wingless.
  3. A vast pool of lineage-specific microproteins encoded by long non-coding RNAs in plants.
  4. Unraveling the hidden role of a uORF-encoded peptide as a kinase inhibitor of PKCs.
  5. Micropeptide ASAP encoded by LINC00467 promotes colorectal cancer progression by directly modulating ATP synthase activity.
  6. SPENCER: a comprehensive database for small peptides encoded by noncoding RNAs in cancer patients.
  7. TransLnc: a comprehensive resource for translatable lncRNAs extends immunopeptidome.
  1. Biochemistry (Mosc). 2021 Sep;86(9): 1139-1150
    Little but Loud. The Diversity of Functions of Small Proteins and Peptides - Translational Products of Short Reading Frames.
    Petr V Sergiev, Maria P Rubtsova.
      Cell functioning is tightly regulated process. For many years, research in the fields of proteomics and functional genomics has been focused on the role of proteins in cell functioning. The advances in science have led to the uncovering that short open reading frames, previously considered non-functional, serve a variety of functions. Short reading frames in polycistronic mRNAs often regulate their stability and translational efficiency of the main reading frame. The improvement of proteomic analysis methods has made it possible to identify the products of translation of short open reading frames in quantities that suggest the existence of functional role of those peptides and short proteins. Studies demonstrating their role unravel a new level of the regulation of cell functioning and its adaptation to changing conditions. This review is devoted to the analysis of functions of recently discovered peptides and short proteins.
    Keywords:  alternative proteins; long non-coding RNAs; peptides; small open reading frames
    DOI:  https://doi.org/10.1134/S0006297921090091
  2. Nat Commun. 2021 Sep 27. 12(1): 5660
    Pegasus, a small extracellular peptide enhancing short-range diffusion of Wingless.
    Emile G Magny, Ana Isabel Platero, Sarah A Bishop, Jose I Pueyo, Daniel Aguilar-Hidalgo, Juan Pablo Couso.
      Small Open Reading Frames (smORFs) coding for peptides of less than 100 amino-acids are an enigmatic and pervasive gene class, found in the tens of thousands in metazoan genomes. Here we reveal a short 80 amino-acid peptide (Pegasus) which enhances Wingless/Wnt1 protein short-range diffusion and signalling. During Drosophila wing development, Wingless has sequential functions, including late induction of proneural gene expression and wing margin development. Pegasus mutants produce wing margin defects and proneural expression loss similar to those of Wingless. Pegasus is secreted, and co-localizes and co-immunoprecipitates with Wingless, suggesting their physical interaction. Finally, measurements of fixed and in-vivo Wingless gradients support that Pegasus increases Wingless diffusion in order to enhance its signalling. Our results unveil a new element in Wingless signalling and clarify the patterning role of Wingless diffusion, while corroborating the link between small open reading frame peptides, and regulation of known proteins with membrane-related functions.
    DOI:  https://doi.org/10.1038/s41467-021-25785-z
  3. Nucleic Acids Res. 2021 Sep 27. pii: gkab816. [Epub ahead of print]
    A vast pool of lineage-specific microproteins encoded by long non-coding RNAs in plants.
    Igor Fesenko, Svetlana A Shabalina, Anna Mamaeva, Andrey Knyazev, Anna Glushkevich, Irina Lyapina, Rustam Ziganshin, Sergey Kovalchuk, Daria Kharlampieva, Vassili Lazarev, Michael Taliansky, Eugene V Koonin.
      Pervasive transcription of eukaryotic genomes results in expression of long non-coding RNAs (lncRNAs) most of which are poorly conserved in evolution and appear to be non-functional. However, some lncRNAs have been shown to perform specific functions, in particular, transcription regulation. Thousands of small open reading frames (smORFs, <100 codons) located on lncRNAs potentially might be translated into peptides or microproteins. We report a comprehensive analysis of the conservation and evolutionary trajectories of lncRNAs-smORFs from the moss Physcomitrium patens across transcriptomes of 479 plant species. Although thousands of smORFs are subject to substantial purifying selection, the majority of the smORFs appear to be evolutionary young and could represent a major pool for functional innovation. Using nanopore RNA sequencing, we show that, on average, the transcriptional level of conserved smORFs is higher than that of non-conserved smORFs. Proteomic analysis confirmed translation of 82 novel species-specific smORFs. Numerous conserved smORFs containing low complexity regions (LCRs) or transmembrane domains were identified, the biological functions of a selected LCR-smORF were demonstrated experimentally. Thus, microproteins encoded by smORFs are a major, functionally diverse component of the plant proteome.
    DOI:  https://doi.org/10.1093/nar/gkab816
  4. Proc Natl Acad Sci U S A. 2021 Oct 05. pii: e2018899118. [Epub ahead of print]118(40):
    Unraveling the hidden role of a uORF-encoded peptide as a kinase inhibitor of PKCs.
    Divya Ram Jayaram, Sigal Frost, Chanan Argov, Vijayasteltar Belsamma Liju, Nikhil Ponnoor Anto, Amitha Muraleedharan, Assaf Ben-Ari, Rose Sinay, Ilan Smoly, Ofra Novoplansky, Noah Isakov, Debra Toiber, Chen Keasar, Moshe Elkabets, Esti Yeger-Lotem, Etta Livneh.
      Approximately 40% of human messenger RNAs (mRNAs) contain upstream open reading frames (uORFs) in their 5' untranslated regions. Some of these uORF sequences, thought to attenuate scanning ribosomes or lead to mRNA degradation, were recently shown to be translated, although the function of the encoded peptides remains unknown. Here, we show a uORF-encoded peptide that exhibits kinase inhibitory functions. This uORF, upstream of the protein kinase C-eta (PKC-η) main ORF, encodes a peptide (uPEP2) containing the typical PKC pseudosubstrate motif present in all PKCs that autoinhibits their kinase activity. We show that uPEP2 directly binds to and selectively inhibits the catalytic activity of novel PKCs but not of classical or atypical PKCs. The endogenous deletion of uORF2 or its overexpression in MCF-7 cells revealed that the endogenously translated uPEP2 reduces the protein levels of PKC-η and other novel PKCs and restricts cell proliferation. Functionally, treatment of breast cancer cells with uPEP2 diminished cell survival and their migration and synergized with chemotherapy by interfering with the response to DNA damage. Furthermore, in a xenograft of MDA-MB-231 breast cancer tumor in mice models, uPEP2 suppressed tumor progression, invasion, and metastasis. Tumor histology showed reduced proliferation, enhanced cell death, and lower protein expression levels of novel PKCs along with diminished phosphorylation of PKC substrates. Hence, our study demonstrates that uORFs may encode biologically active peptides beyond their role as translation regulators of their downstream ORFs. Together, we point to a unique function of a uORF-encoded peptide as a kinase inhibitor, pertinent to cancer therapy.
    Keywords:  PKC; kinase inhibitor; pseudosubstrate; uORF
    DOI:  https://doi.org/10.1073/pnas.2018899118
  5. J Clin Invest. 2021 Sep 30. pii: e152911. [Epub ahead of print]
    Micropeptide ASAP encoded by LINC00467 promotes colorectal cancer progression by directly modulating ATP synthase activity.
    Qiwei Ge, Dingjiacheng Jia, Dong Cen, Yadong Qi, Chengyu Shi, Junhong Li, Lingjie Sang, Luo-Jia Yang, Jiamin He, Aifu Lin, Shujie Chen, Liangjing Wang.
      Emerging evidence has shown that open reading frames inside lncRNA could encode micropeptides. However, their roles in cellular energy metabolism and tumor progression remain largely unknown. Here, we identified a 94-amino acid-length micropeptide encoded by lncRNA LINC00467 in colorectal cancer. We also characterized its conservation across higher mammals, localization to mitochondria, and the concerted local functions. This peptide enhanced the ATP synthase construction by interacting with the subunit α and γ (ATP5A and ATP5C), increased ATP synthase activity and mitochondrial oxygen consumption rate, and thereby promoted colorectal cancer cell proliferation. Hence, this micropeptide was termed as "ATP synthase associated peptide" (ASAP). Furthermore, loss of ASAP suppressed patient-derived xenograft growth with attenuated ATP synthase activity and mitochondrial ATP production. Clinically, high expression of ASAP and LINC00467 predicted poor prognosis of colorectal cancer patients. Taken together, our findings revealed a colorectal cancer-associated micropeptide as a vital player in mitochondrial metabolism and provided a therapeutic target for colorectal cancer.
    Keywords:  Colorectal cancer; Gastroenterology; Noncoding RNAs; Oncology
    DOI:  https://doi.org/10.1172/JCI152911
  6. Nucleic Acids Res. 2021 Sep 27. pii: gkab822. [Epub ahead of print]
    SPENCER: a comprehensive database for small peptides encoded by noncoding RNAs in cancer patients.
    Xiaotong Luo, Yuantai Huang, Huiqin Li, Yihai Luo, Zhixiang Zuo, Jian Ren, Yubin Xie.
      As an increasing number of noncoding RNAs (ncRNAs) have been suggested to encode short bioactive peptides in cancer, the exploration of ncRNA-encoded small peptides (ncPEPs) is emerging as a fascinating field in cancer research. To assist in studies on the regulatory mechanisms of ncPEPs, we describe here a database called SPENCER (http://spencer.renlab.org). Currently, SPENCER has collected a total of 2806 mass spectrometry (MS) data points from 55 studies, covering 1007 tumor samples and 719 normal samples. Using an MS-based proteomics analysis pipeline, SPENCER identified 29 526 ncPEPs across 15 different cancer types. Specifically, 22 060 of these ncPEPs were experimentally validated in other studies. By comparing tumor and normal samples, the identified ncPEPs were divided into four expression groups: tumor-specific, upregulated in cancer, downregulated in cancer, and others. Additionally, since ncPEPs are potential targets for neoantigen-based cancer immunotherapy, SPENCER also predicted the immunogenicity of all the identified ncPEPs by assessing their MHC-I binding affinity, stability, and TCR recognition probability. As a result, 4497 ncPEPs curated in SPENCER were predicted to be immunogenic. Overall, SPENCER will be a useful resource for investigating cancer-associated ncPEPs and may boost further research in cancer.
    DOI:  https://doi.org/10.1093/nar/gkab822
  7. Nucleic Acids Res. 2021 Sep 27. pii: gkab847. [Epub ahead of print]
    TransLnc: a comprehensive resource for translatable lncRNAs extends immunopeptidome.
    Dezhong Lv, Zhenghong Chang, Yangyang Cai, Junyi Li, Liping Wang, Qiushuang Jiang, Kang Xu, Na Ding, Xia Li, Juan Xu, Yongsheng Li.
      LncRNAs are not only well-known as non-coding elements, but also serve as templates for peptide translation, playing important roles in fundamental cellular processes and diseases. Here, we describe a database, TransLnc (http://bio-bigdata.hrbmu.edu.cn/TransLnc/), which aims to provide comprehensive experimentally supported and predicted lncRNA peptides in multiple species. TransLnc currently documents approximate 583 840 peptides encoded by 33 094 lncRNAs. Six types of direct and indirect evidences supporting the coding potential of lncRNAs were integrated, and 65.28% peptides entries were with at least one type of evidence. Considering the strong tissue-specific expression of lncRNAs, TransLnc allows users to access lncRNA peptides in any of the 34 tissues involved in. In addition, both the unique characteristic and homology relationship were also predicted and provided. Importantly, TransLnc provides computationally predicted tumour neoantigens from peptides encoded by lncRNAs, which would provide novel insights into cancer immunotherapy. There were 220 791 and 237 915 candidate neoantigens binding by major histocompatibility complex (MHC) class I or II molecules, respectively. Several flexible tools were developed to aid retrieve and analyse, particularly lncRNAs tissue expression patterns, clinical relevance across cancer types. TransLnc will serve as a valuable resource for investigating the translation capacity of lncRNAs and greatly extends the cancer immunopeptidome.
    DOI:  https://doi.org/10.1093/nar/gkab847
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