bims-micpro 2024-08-18 papers

Nat Commun. 2024 Aug 09. 15(1): 6839

Rp3: Ribosome profiling-assisted proteogenomics improves coverage and confidence during microprotein discovery.

Eduardo Vieira de Souza, Angie L Bookout, Christopher A Barnes, Brendan Miller, Pablo Machado, Luiz A Basso, Cristiano V Bizarro, Alan Saghatelian.

There has been a dramatic increase in the identification of non-canonical translation and a significant expansion of the protein-coding genome. Among the strategies used to identify unannotated small Open Reading Frames (smORFs) that encode microproteins, Ribosome profiling (Ribo-Seq) is the gold standard for the annotation of novel coding sequences by reporting on smORF translation. In Ribo-Seq, ribosome-protected footprints (RPFs) that map to multiple genomic sites are removed since they cannot be unambiguously assigned to a specific genomic location. Furthermore, RPFs necessarily result in short (25-34 nucleotides) reads, increasing the chance of multi-mapping alignments, such that smORFs residing in these regions cannot be identified by Ribo-Seq. Moreover, it has been challenging to identify protein evidence for Ribo-Seq. To solve this, we developed Rp3, a pipeline that integrates proteogenomics and Ribosome profiling to provide unambiguous evidence for a subset of microproteins missed by current Ribo-Seq pipelines. Here, we show that Rp3 maximizes proteomics detection and confidence of microprotein-encoding smORFs.

DOI: https://doi.org/10.1038/s41467-024-50301-4

J Hematol Oncol. 2024 Aug 12. 17(1): 66

LncRNA-encoded peptides in cancer.

Yaguang Zhang.

Long non-coding RNAs (lncRNAs), once considered transcriptional noise, have emerged as critical regulators of gene expression and key players in cancer biology. Recent breakthroughs have revealed that certain lncRNAs can encode small open reading frame (sORF)-derived peptides, which are now understood to contribute to the pathogenesis of various cancers. This review synthesizes current knowledge on the detection, functional roles, and clinical implications of lncRNA-encoded peptides in cancer. We discuss technological advancements in the detection and validation of sORFs, including ribosome profiling and mass spectrometry, which have facilitated the discovery of these peptides. The functional roles of lncRNA-encoded peptides in cancer processes such as gene transcription, translation regulation, signal transduction, and metabolic reprogramming are explored in various types of cancer. The clinical potential of these peptides is highlighted, with a focus on their utility as diagnostic biomarkers, prognostic indicators, and therapeutic targets. The challenges and future directions in translating these findings into clinical practice are also discussed, including the need for large-scale validation, development of sensitive detection methods, and optimization of peptide stability and delivery.

Keywords: Application; Cancer; Long non-coding RNA; Peptide; Small open reading frame

DOI: https://doi.org/10.1186/s13045-024-01591-0

Cancers (Basel). 2024 Jul 26. pii: 2660. [Epub ahead of print]16(15):

Exploring the Dark Matter of Human Proteome: The Emerging Role of Non-Canonical Open Reading Frame (ncORF) in Cancer Diagnosis, Biology, and Therapy.

Anni Ge, Curtis Chan, Xiaolong Yang.

Cancer develops from abnormal cell growth in the body, causing significant mortalities every year. To date, potent therapeutic approaches have been developed to eradicate tumor cells, but intolerable toxicity and drug resistance can occur in treated patients, limiting the efficiency of existing treatment strategies. Therefore, searching for novel genes critical for cancer progression and therapeutic response is urgently needed for successful cancer therapy. Recent advances in bioinformatics and proteomic techniques have allowed the identification of a novel category of peptides encoded by non-canonical open reading frames (ncORFs) from historically non-coding genomic regions. Surprisingly, many ncORFs express functional microproteins that play a vital role in human cancers. In this review, we provide a comprehensive description of different ncORF types with coding capacity and technological methods in discovering ncORFs among human genomes. We also summarize the carcinogenic role of ncORFs such as pTINCR and HOXB-AS3 in regulating hallmarks of cancer, as well as the roles of ncORFs such as HOXB-AS3 and CIP2A-BP in cancer diagnosis and prognosis. We also discuss how ncORFs such as AKT-174aa and DDUP are involved in anti-cancer drug response and the underestimated potential of ncORFs as therapeutic targets.

Keywords: cancer biology; cancer diagnosis; cancer prognosis; cancer therapy; human proteome; micropeptide; microprotein; ncORF

DOI: https://doi.org/10.3390/cancers16152660

PLoS Pathog. 2024 Aug 13. 20(8): e1012461

A small protein encoded by PCBP1-AS1 is identified as a key regulator of influenza virus replication via enhancing autophagy.

Xiaojuan Chi, Guiying Huang, Liwei Wang, Xinge Zhang, Jiayin Liu, Zhihui Yin, Guijie Guo, Yuhai Chen, Song Wang, Ji-Long Chen.

Many annotated long noncoding RNAs (lncRNAs) contain small open reading frames (sORFs), some of which have been demonstrated to encode small proteins or micropeptides with fundamental biological importance. However, functions of lncRNAs-encoded small proteins or micropeptides in viral pathogenesis remain largely unexplored. Here, we identified a 110-amino acid small protein as a key regulator of influenza A virus (IAV) replication. This small protein that we call PESP was encoded by the putative lncRNA PCBP1-AS1. It was observed that both PCBP1-AS1 and PESP were significantly upregulated by IAV infection. Furthermore, they were markedly induced by treatment with either type I or type III interferon. Overexpression of either PCBP1-AS1 or PESP alone significantly enhanced IAV replication. In contrast, shRNA-mediated knockdown of PCBP1-AS1 or CRISPR/Cas9-mediated knockout of PESP markedly inhibited the viral production. Moreover, the targeted deletion or mutation of the sORF within the PCBP1-AS1 transcript, which resulted in the disruption of PESP expression, significantly diminished the capacity of PCBP1-AS1 to enhance IAV replication, underscoring the indispensable role of PESP in the facilitation of IAV replication by PCBP1-AS1. Interestingly, overexpression of PESP enhanced the IAV-induced autophagy by increasing the expression of ATG7, an essential autophagy effector enzyme. We also found that the 7-22 amino acids at the N-terminus of PESP were crucial for its functionality in modulating ATG7 expression and action as an enhancer of IAV replication. Additionally, HSP90AA1, a protein identified previously as a facilitator of autophagy, was found to interact with PESP, resulting in the stabilization of PESP and consequently an increase in the production of IAV. These data reveal a critical lncRNA-encoded small protein that is induced and exploited by IAV during its infection, and provide a significant insight into IAV-host interaction network.

DOI: https://doi.org/10.1371/journal.ppat.1012461