bims-micpro 2021-01-10 papers

Issue of 2021‒01‒10
three papers selected by
Thomas Martinez
Salk Institute for Biological Studies

Cell Metab. 2021 Jan 05. pii: S1550-4131(20)30663-X. [Epub ahead of print]33(1): 128-144.e9

An Upstream Open Reading Frame in Phosphatase and Tensin Homolog Encodes a Circuit Breaker of Lactate Metabolism.

Nunu Huang, Fanying Li, Maolei Zhang, Huangkai Zhou, Zhipeng Chen, Xiaoyan Ma, Lixuan Yang, Xujia Wu, Jian Zhong, Feizhe Xiao, Xuesong Yang, Kun Zhao, Xixi Li, Xin Xia, Zexian Liu, Song Gao, Nu Zhang.

The metabolic role of micropeptides generated from untranslated regions remains unclear. Here we describe MP31, a micropeptide encoded by the upstream open reading frame (uORF) of phosphatase and tensin homolog (PTEN) acting as a "circuit breaker" that limits lactate-pyruvate conversion in mitochondria by competing with mitochondrial lactate dehydrogenase (mLDH) for nicotinamide adenine dinucleotide (NAD+). Knocking out the MP31 homolog in mice enhanced global lactate metabolism, manifesting as accelerated oxidative phosphorylation (OXPHOS) and increased lactate consumption and production. Conditional knockout (cKO) of MP31 homolog in mouse astrocytes initiated gliomagenesis and shortened the overall survival of the animals, establishing a tumor-suppressing role for MP31. Recombinant MP31 administered intraperitoneally penetrated the blood-brain barrier and inhibited mice GBM xenografts without neurological toxicity, suggesting the clinical implication and application of this micropeptide. Our findings reveal a novel mode of MP31-orchestrated lactate metabolism reprogramming in glioblastoma.

Keywords: LDH; MP31; OXPHOS; PTEN; glioblastoma; lactate oxidation; tumorigenesis; uORF

DOI: https://doi.org/10.1016/j.cmet.2020.12.008

Curr Opin Chem Biol. 2021 Jan 02. pii: S1367-5931(20)30161-7. [Epub ahead of print]60 122-130

Recent advances in mass spectrometry-based peptidomics workflows to identify short-open-reading-frame-encoded peptides and explore their functions.

Bertrand Fabre, Jean-Philippe Combier, Serge Plaza.

Short open reading frame (sORF)-encoded polypeptides (SEPs) have recently emerged as key regulators of major cellular processes. Computational methods for the annotation of sORFs combined with transcriptomics and ribosome profiling approaches predicted the existence of tens of thousands of SEPs across the kingdom of life. Although, we still lack unambiguous evidence for most of them. The method of choice to validate the expression of SEPs is mass spectrometry (MS)-based peptidomics. Peptides are less abundant than proteins, which tends to hinder their detection. Therefore, optimization and enrichment methods are necessary to validate the existence of SEPs. In this article, we discuss the challenges for the detection of SEPs by MS and recent developments of biochemical approaches applied to the study of these peptides. We detail the advances made in the different key steps of a typical peptidomics workflow and highlight possible alternatives that have not been explored yet.

Keywords: Mass spectrometry; Microprotein; Peptidomics; Short open reading frame–encoded polypeptide (SEP)

DOI: https://doi.org/10.1016/j.cbpa.2020.12.002

Curr Genet. 2021 Jan 09.

Origin of translational control by eIF2α phosphorylation: insights from genome-wide translational profiling studies in fission yeast.

Katsura Asano.

During amino acid limitation, the protein kinase Gcn2 phosphorylates the α subunit of eIF2, thereby regulating mRNA translation. In yeast Saccharomyces cerevisiae and mammals, eIF2α phosphorylation regulates translation of related transcription factors Gcn4 and Atf4 through upstream open reading frames (uORFs) to activate transcription genome wide. However, mammals encode three more eIF2α kinases activated by distinct stimuli. Did the translational control system involving eIF2α phosphorylation evolve from so simple (as found in yeast S. cerevisiae) to complex (as found in humans)? Recent genome-wide translational profiling studies of amino acid starvation response in the fission yeast Schizosaccharomyces pombe provide an unexpected answer to this question.

Keywords: Evolution; Schizosaccharomyces pombe; Translational control; eIF2α kinase; uORF

DOI: https://doi.org/10.1007/s00294-020-01149-w