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<p>Eukaryotic mRNAs typically encode a single functional polypeptide, a principle challenged by the discovery of widespread non-canonical peptide-coding ORFs within 5’UTRs. However, their functional significance at the protein level remains underexplored. Using a four-layered pipeline, we identify 14 human transcripts predominantly transcribed in polycistronic forms, each encoding two conserved proteins. Focusing on the <i>SLC35A4</i> transcript, we show that its 5’UTR encodes a mitochondrial inner membrane-localized microprotein that we name STREMI (<Emphasis Type="Underline">S</Emphasis>LC35A4 s<Emphasis Type="Underline">t</Emphasis>ress <Emphasis Type="Underline">re</Emphasis>sponse regulating <Emphasis Type="Underline">M</Emphasis>ICOS <Emphasis Type="Underline">i</Emphasis>nteractor). Sharing topology and motifs with the MICOS core subunit MIC10, STREMI regulates mitochondrial cristae morphogenesis in mice and human cells. Additionally, the STREMI-encoding uORF mediates stress-responsive translation of <i>SLC35A4</i>—a Golgi nucleotide sugar transporter—upregulating its translation during the integrated stress response. Evolutionary analyses indicate that these bicistronic transcripts likely arose through transcriptional readthrough following retroposition. We propose a mechanism of “gene symbiosis” that enables functional partitioning and coordinated translation of protein pairs from bicistronic transcripts.</p>

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STREMI: a dual-function upstream ORF-encoded regulator of mitochondrial cristae architecture

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年5月2日

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  • Ruiyang Guo,
  • Yabo Guo,
  • Runguo Shu,
  • Jiajia Qian,
  • Jiawei Wang,
  • Ruobing Li,
  • Ti Qin,
  • Ziyi Wang,
  • Hongtao Tian,
  • Mengchen Wu,
  • Long Zhou,
  • Xiaogang Guo,
  • Shan Zhang

摘要

Eukaryotic mRNAs typically encode a single functional polypeptide, a principle challenged by the discovery of widespread non-canonical peptide-coding ORFs within 5’UTRs. However, their functional significance at the protein level remains underexplored. Using a four-layered pipeline, we identify 14 human transcripts predominantly transcribed in polycistronic forms, each encoding two conserved proteins. Focusing on the SLC35A4 transcript, we show that its 5’UTR encodes a mitochondrial inner membrane-localized microprotein that we name STREMI (SLC35A4 stress response regulating MICOS interactor). Sharing topology and motifs with the MICOS core subunit MIC10, STREMI regulates mitochondrial cristae morphogenesis in mice and human cells. Additionally, the STREMI-encoding uORF mediates stress-responsive translation of SLC35A4—a Golgi nucleotide sugar transporter—upregulating its translation during the integrated stress response. Evolutionary analyses indicate that these bicistronic transcripts likely arose through transcriptional readthrough following retroposition. We propose a mechanism of “gene symbiosis” that enables functional partitioning and coordinated translation of protein pairs from bicistronic transcripts.