A short ORF-encoded transcriptional regulator

Koh, Minseob; Ahmad, Insha; Ko, Yeonjin; Zhang, Yuxiang; Martínez, Thomas F.; Diedrich, Jolene K.; Chu, Qian; Moresco, James J.; Erb, Michael; Saghatelian, Alan; Schultz, Peter G.; Bollong, Michael J.

doi:10.1073/pnas.2021943118

Cited by 43 publications

(36 citation statements)

References 36 publications

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“…Ribosome profiling and high-throughput genetic analyses has revealed hundreds of functional microproteins in human cells [ 76 , 77 ]. Documented functions for microproteins include phagocytosis [ 70 ], autophagy [ 71 ], actin-based motility [ 72 ], mRNA decapping [ 78 ], proteolytic processing [ 79 ], mitotic chromosome segregation [ 73 ], mitochondrial morphology control [ 76 ], plant hormone signaling [ 80 ], transcriptional control [ 81 ], and cancer cell survival [ 77 ], among many others [ 82 , 83 ]. Microproteins derived from noncanonical coding regions represent a substantial fraction of major histocompatibility complex (MHC) class I–associated tumor-specific antigens [ 84 , 85 ].…”

Section: Discussionmentioning

confidence: 99%

The microprotein Nrs1 rewires the G1/S transcriptional machinery during nitrogen limitation in budding yeast

et al. 2022

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Commitment to cell division at the end of G1 phase, termed Start in the budding yeast Saccharomyces cerevisiae, is strongly influenced by nutrient availability. To identify new dominant activators of Start that might operate under different nutrient conditions, we screened a genome-wide ORF overexpression library for genes that bypass a Start arrest caused by absence of the G1 cyclin Cln3 and the transcriptional activator Bck2. We recovered a hypothetical gene YLR053c, renamed NRS1 for Nitrogen-Responsive Start regulator 1, which encodes a poorly characterized 108 amino acid microprotein. Endogenous Nrs1 was nuclear-localized, restricted to poor nitrogen conditions, induced upon TORC1 inhibition, and cell cycle-regulated with a peak at Start. NRS1 interacted genetically with SWI4 and SWI6, which encode subunits of the main G1/S transcription factor complex SBF. Correspondingly, Nrs1 physically interacted with Swi4 and Swi6 and was localized to G1/S promoter DNA. Nrs1 exhibited inherent transactivation activity, and fusion of Nrs1 to the SBF inhibitor Whi5 was sufficient to suppress other Start defects. Nrs1 appears to be a recently evolved microprotein that rewires the G1/S transcriptional machinery under poor nitrogen conditions.

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Section: Discussionmentioning

confidence: 99%

The microprotein Nrs1 rewires the G1/S transcriptional machinery during nitrogen limitation in budding yeast

et al. 2022

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“…Another example is the 46 aa long SEP, Myoregulin (MNL) encoded from a presumed lncRNA and shown to be expressed in skeletal muscle and involved in the regulation of Ca2+ handling by inhibiting the pump activity of SERCA, a membrane pump that controls muscle relaxation by regulating Ca2+ uptake into the sarcoplasmic reticulum (SR) (Anderson et al, 2015). Very recently, Koh and collaborators identified short ORF-encoded histone binding protein (SEHBP) as a transcriptional regulator (Koh et al, 2021). In their study, the authors developed an experimental assay identifying partners of SEP in cells by introducing a photo-crosslinking non-canonical amino acid into SEP transgenes and using enhanced affinity purification mass spectrometry-based mapping strategy.…”

Section: Implication Of Sorfs and Their Encoded Peptides In Humans: Relevant Examplesmentioning

confidence: 99%

Small Open Reading Frames, How to Find Them and Determine Their Function

et al. 2022

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Advances in genomics and molecular biology have revealed an abundance of small open reading frames (sORFs) across all types of transcripts. While these sORFs are often assumed to be non-functional, many have been implicated in physiological functions and a significant number of sORFs have been described in human diseases. Thus, sORFs may represent a hidden repository of functional elements that could serve as therapeutic targets. Unlike protein-coding genes, it is not necessarily the encoded peptide of an sORF that enacts its function, sometimes simply the act of translating an sORF might have a regulatory role. Indeed, the most studied sORFs are located in the 5′UTRs of coding transcripts and can have a regulatory impact on the translation of the downstream protein-coding sequence. However, sORFs have also been abundantly identified in non-coding RNAs including lncRNAs, circular RNAs and ribosomal RNAs suggesting that sORFs may be diverse in function. Of the many different experimental methods used to discover sORFs, the most commonly used are ribosome profiling and mass spectrometry. These can confirm interactions between transcripts and ribosomes and the production of a peptide, respectively. Extensions to ribosome profiling, which also capture scanning ribosomes, have further made it possible to see how sORFs impact the translation initiation of mRNAs. While high-throughput techniques have made the identification of sORFs less difficult, defining their function, if any, is typically more challenging. Together, the abundance and potential function of many of these sORFs argues for the necessity of including sORFs in gene annotations and systematically characterizing these to understand their potential functional roles. In this review, we will focus on the high-throughput methods used in the detection and characterization of sORFs and discuss techniques for validation and functional characterization.

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“…However, the actual existence of the vast majority of putative uORF-derived peptides await further experimental evidence including a Ppp1r15a uORF-derived peptide. Challenges inherent to detection of uORFderived peptides include limited tagging, enrichment strategies, and rapid turnover 16,17,[35][36][37][38] . Indeed, Ppp1r15a uORF contains a degron signal that could cause the peptide to be particularly short-lived (Suppl Fig.…”

Section: Effects Of Ppp1r15a Uorf On Mhc-i Immunopeptidomementioning

confidence: 99%

Translation rescue by targeting Ppp1r15a upstream open reading frame in vivo

Kidwell

Yadav

Maier

et al. 2021

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The eIF2 initiation complex is central to maintaining a functional translation machinery. Extreme stress such as life-threatening sepsis exposes vulnerabilities in this tightly regulated system, resulting in an imbalance between the opposing actions of kinases and phosphatases on the main regulatory subunit eIF2α. Here, we report that translation shutdown is a hallmark of established sepsis-induced kidney injury brought about by excessive eIF2α phosphorylation and sustained by blunted expression of the counterregulatory phosphatase subunit Ppp1r15a. We determined that the blunted Ppp1r15a expression persists because of the presence of an upstream open reading frame (uORF). Overcoming this barrier with genetic approaches enabled the derepression of Ppp1r15a, salvaged translation and improved kidney function in an endotoxemia model. We also found that the loss of this uORF has broad effects on the composition and phosphorylation status of the immunopeptidome that extended beyond the eIF2α axis. Collectively, our findings define the breath and potency of the highly conserved Ppp1r15a uORF and provide a paradigm for the design of uORF-based translation rheostat strategies. The ability to accurately control the dynamics of translation during sepsis will open new paths for the development of therapies at codon level precision.

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A short ORF-encoded transcriptional regulator

Cited by 43 publications

References 36 publications

The microprotein Nrs1 rewires the G1/S transcriptional machinery during nitrogen limitation in budding yeast

The microprotein Nrs1 rewires the G1/S transcriptional machinery during nitrogen limitation in budding yeast

Small Open Reading Frames, How to Find Them and Determine Their Function

Translation rescue by targeting Ppp1r15a upstream open reading frame in vivo

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