bims-micpro 2024-10-27 papers

Issue of 2024‒10‒27
six papers selected by
Thomas Farid Martínez, University of California, Irvine

Cell Death Discov. 2024 Oct 23. 10(1): 450

Long non-coding RNA-encoded micropeptides: functions, mechanisms and implications.

Yinan Xiao, Yaru Ren, Wenteng Hu, Athanasios R Paliouras, Wenyang Zhang, Linghui Zhong, Kaixin Yang, Li Su, Peng Wang, Yonghong Li, Minjie Ma, Lei Shi.

Long non-coding RNAs (lncRNAs) are typically described as RNA transcripts exceeding 200 nucleotides in length, which do not code for proteins. Recent advancements in technology, including ribosome RNA sequencing and ribosome nascent-chain complex sequencing, have demonstrated that many lncRNAs retain small open reading frames and can potentially encode micropeptides. Emerging studies have revealed that these micropeptides, rather than lncRNAs themselves, are responsible for vital functions, including but not limited to regulating homeostasis, managing inflammation and the immune system, moderating metabolism, and influencing tumor progression. In this review, we initially outline the rapidly advancing computational analytical methods and public tools to predict and validate the potential encoding of lncRNAs. We then focus on the diverse functions of micropeptides and their underlying mechanisms in the pathogenesis of disease. This review aims to elucidate the functions of lncRNA-encoded micropeptides and explore their potential applications as therapeutic targets in cancer.

DOI: https://doi.org/10.1038/s41420-024-02175-0

Adv Sci (Weinh). 2024 Oct 24. e2407012

HCP5 Derived Novel Microprotein Triggers Progression of Gastric Cancer through Regulating Ferroptosis.

Qiuhui Li, Guoqing Guo, Yuli Chen, Lu Lu, Hanyang Li, Zihan Zhou, Jiahao Guo, Xiongkang Gan, Yanming Hu, Qiunuo Li, Ming Sun, Xianghua Liu.

The context of long noncoding RNAs (lncRNAs) contains many unannotated open reading frames (ORFs). These ORFs potentially encode novel proteins or peptides with crucial roles in various human cancers, yet the translational potential of these lncRNAs and the functions of the protein products remain largely unexplored, especially in gastric cancer (GC). In this study, a comprehensive analysis is performed and identified a GC associated lncRNA known as HCP5, which contains a non-canonical ORF. Further analysis showed that HCP5-132aa, a microprotein encoded by HCP5 harboring this ORF, is highly expressed in GC cells and tissues, and can promote the proliferation of GC cells by inhibiting ferroptosis. Mechanistically, HCP5-132aa enhances the interaction between YBX1 and ELAVL1, facilitates recognition of YBX1 at the m5C site in the 3'UTR of SLC7A11 and G6PD mRNA, and preserves their stability via ELAVL1. By employing a Cas9/sgRNA delivery system with AAV in vivo, effectively knocked out the HCP5-132aa and inhibition of tumor growth in a patient-derived xenograft model are achieved. These findings demonstrate that the novel protein HCP5-132aa, derived from lncRNA HCP5, mediates the repression of ferroptosis, thereby driving the progression of GC and identifying a new potential therapeutic target for its treatment.

Keywords: HCP5‐132aa; YBX1; ferroptosis; gastric cancer; m5C modification

DOI: https://doi.org/10.1002/advs.202407012

Plant Cell. 2024 Oct 24. pii: koae289. [Epub ahead of print]

Ribosome binding of phasiRNA precursors accelerates the 24-nt phasiRNA burst in meiotic maize anthers.

Yingjia Han, Siqi Jiang, Xiaomei Dong, Xing Dai, Shunxi Wang, Ying Zheng, Ge Yan, Shengben Li, Liuji Wu, Virginia Walbot, Blake C Meyers, Mei Zhang.

Reproductive phasiRNAs (phased, small interfering RNAs), produced from numerous PHAS loci, are essential for plant anther development. PHAS transcripts are enriched on endoplasmic reticulum-bound ribosomes in maize (Zea mays), but the impact of ribosome binding on phasiRNA biogenesis remains elusive. Through ribosome profiling of maize anthers at 10 developmental stages, we demonstrated that 24-PHAS transcripts are bound by ribosomes, with patterns corresponding to the timing and abundance of 24-PHAS transcripts. Ribosome binding to 24-PHAS transcripts is conserved among different maize inbred lines, with ribosomes enriched upstream of miR2275 target sites. We detected short open reading frames (sORFs) in the ribosome-binding regions of some 24-PHAS transcripts and observed a 3-nt periodicity in most sORFs, but mass spectrometry failed to detect peptides corresponding to the sORFs. Deletion of the entire ribosome-binding region of 24PHAS_NO296 locus eliminated ribosome binding and decreased 24-nt phasiRNA production, without affecting 24PHAS_NO296 transcript levels. In contrast, disrupting only the sORFs in 24PHAS_NO296 did not substantially affect the generation of 24-nt phasiRNAs. A newly formed sORF in these mutants may have re-directed ribosome binding to its transcripts. Overall, these findings demonstrate that sORFs facilitate ribosome binding to 24-PHAS transcripts, thereby promoting phasiRNA biogenesis in meiotic anthers.

DOI: https://doi.org/10.1093/plcell/koae289

Nature. 2024 Oct 23.

Nuclear release of eIF1 restricts start-codon selection during mitosis.

Jimmy Ly, Kehui Xiang, Kuan-Chung Su, Gunter B Sissoko, David P Bartel, Iain M Cheeseman.

Regulated start-codon selection has the potential to reshape the proteome through the differential production of upstream open reading frames, canonical proteins, and alternative translational isoforms1-3. However, conditions under which start codon selection is altered remain poorly defined. Here, using transcriptome-wide translation-initiation-site profiling4, we reveal a global increase in the stringency of start-codon selection during mammalian mitosis. Low-efficiency initiation sites are preferentially repressed in mitosis, resulting in pervasive changes in the translation of thousands of start sites and their corresponding protein products. This enhanced stringency of start-codon selection during mitosis results from increased association between the 40S ribosome and the key regulator of start-codon selection, eIF1. We find that increased eIF1-40S ribosome interaction during mitosis is mediated by the release of a nuclear pool of eIF1 upon nuclear envelope breakdown. Selectively depleting the nuclear pool of eIF1 eliminates the change to translational stringency during mitosis, resulting in altered synthesis of thousands of protein isoforms. In addition, preventing mitotic translational rewiring results in substantially increased cell death and decreased mitotic slippage in cells that experience a mitotic delay induced by anti-mitotic chemotherapies. Thus, cells globally control stringency of translation initiation, which has critical roles during the mammalian cell cycle in preserving mitotic cell physiology.

DOI: https://doi.org/10.1038/s41586-024-08088-3

Methods Mol Biol. 2025 ;2859 319-331

Evaluation of Eukaryotic mRNA Coding Potential.

Alex V Kochetov.

It is widely discussed that eukaryotic mRNAs can encode several functional polypeptides. Recent progress in NGS and proteomics techniques has resulted in a huge volume of information on potential alternative translation initiation sites and open reading frames (altORFs). However, these data are still incomprehensive, and the vast majority of eukaryotic mRNAs annotated in conventional databases (e.g., GenBank) contain a single ORF (CDS) encoding a protein larger than some arbitrary threshold (commonly 100 amino acid residues). Indeed, some gene functions may relate to the polypeptides encoded by unannotated altORFs, and insufficient information in nucleotide sequence databanks may limit the interpretation of genomics and transcriptomics data. However, despite the need for special experiments to predict altORFs accurately, there are some simple methods for their preliminary mapping.

Keywords: Gene engineering; Translation; mRNA features; ORF prediction

DOI: https://doi.org/10.1007/978-1-0716-4152-1_18

J Mol Cell Cardiol. 2024 Oct 20. pii: S0022-2828(24)00169-X. [Epub ahead of print]

Another-regulin regulates cardiomyocyte calcium handling via integration of neuroendocrine signaling with SERCA2a activity.

Keira R Hassel, Aaron M Gibson, Jaroslava Šeflová, Ellen E Cho, N Scott Blair, Catherine D Van Raamsdonk, Douglas M Anderson, Seth L Robia, Catherine A Makarewich.

Calcium (Ca2+) dysregulation is a hallmark feature of cardiovascular disease. Intracellular Ca2+ regulation is essential for proper heart function and is controlled by the sarco/endoplasmic reticulum Ca2+ ATPase (SERCA2a). Another-regulin (ALN) is a newly discovered cardiomyocyte-expressed SERCA2a inhibitor, suggesting cardiomyocyte Ca2+-handling is more complex than previously appreciated. To study the role of ALN in cardiomyocytes, we generated ALN null mice (knockout, KO) and found that cardiomyocytes from these animals displayed enhanced Ca2+ cycling and contractility compared to wildtype (WT) mice, indicating enhanced SERCA2a activity. In vitro and in vivo studies show that ALN is post-translationally modified via phosphorylation on Serine 19 (S19), suggesting this contributes to its ability to regulate SERCA2a. Immunoprecipitation and FRET analysis of ALN-WT, phospho-deficient ALN (S19A), or phosphomimetic ALN (S19D) revealed that S19 phosphorylation alters the SERCA2a-ALN interaction, leading to relief of its inhibitory effects. Adeno-associated virus mediated delivery of ALN-WT or phospho-mutant ALN-S19A/D in ALN KO mice showed that cardiomyocyte-specific expression of phospho-deficient ALN-S19A resulted in increased SERCA2a inhibition characterized by reduced rates of cytoplasmic Ca2+ clearance compared to ALN-WT and ALN-S19D expressing cells, further supporting a role for this phosphorylation event in controlling SERCA2a-regulation by ALN. Levels of ALN phosphorylation were markedly increased in cardiomyocytes in response to Gαq agonists (angiotensin II, endothelin-1, phenylephrine) and Gαq-mediated phosphorylation of ALN translated to increased Ca2+ cycling in cardiomyocytes from WT but not ALN KO mice. Collectively, these results indicate that ALN uniquely regulates Ca2+ handling in cardiomyocytes via integration of neuroendocrine signaling with SERCA2a activity.

Keywords: Another-regulin; Calcium; Microprotein; Neuroendocrine signaling; SERCA2a

DOI: https://doi.org/10.1016/j.yjmcc.2024.10.008