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Regulation of the ER stress response by a mitochondrial microprotein

Author

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  • Qian Chu

    (The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology)

  • Thomas F. Martinez

    (The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology)

  • Sammy Weiser Novak

    (The Salk Institute for Biological Studies, Waitt Advanced Biophotonics Center)

  • Cynthia J. Donaldson

    (The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology)

  • Dan Tan

    (The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology)

  • Joan M. Vaughan

    (The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology)

  • Tina Chang

    (The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology)

  • Jolene K. Diedrich

    (The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology)

  • Leo Andrade

    (The Salk Institute for Biological Studies, Waitt Advanced Biophotonics Center)

  • Andrew Kim

    (The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology)

  • Tong Zhang

    (The Salk Institute for Biological Studies, Waitt Advanced Biophotonics Center)

  • Uri Manor

    (The Salk Institute for Biological Studies, Waitt Advanced Biophotonics Center)

  • Alan Saghatelian

    (The Salk Institute for Biological Studies, Clayton Foundation Laboratories for Peptide Biology)

Abstract

Cellular homeostasis relies on having dedicated and coordinated responses to a variety of stresses. The accumulation of unfolded proteins in the endoplasmic reticulum (ER) is a common stress that triggers a conserved pathway called the unfolded protein response (UPR) that mitigates damage, and dysregulation of UPR underlies several debilitating diseases. Here, we discover that a previously uncharacterized 54-amino acid microprotein PIGBOS regulates UPR. PIGBOS localizes to the mitochondrial outer membrane where it interacts with the ER protein CLCC1 at ER–mitochondria contact sites. Functional studies reveal that the loss of PIGBOS leads to heightened UPR and increased cell death. The characterization of PIGBOS reveals an undiscovered role for a mitochondrial protein, in this case a microprotein, in the regulation of UPR originating in the ER. This study demonstrates microproteins to be an unappreciated class of genes that are critical for inter-organelle communication, homeostasis, and cell survival.

Suggested Citation

  • Qian Chu & Thomas F. Martinez & Sammy Weiser Novak & Cynthia J. Donaldson & Dan Tan & Joan M. Vaughan & Tina Chang & Jolene K. Diedrich & Leo Andrade & Andrew Kim & Tong Zhang & Uri Manor & Alan Sagha, 2019. "Regulation of the ER stress response by a mitochondrial microprotein," Nature Communications, Nature, vol. 10(1), pages 1-13, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-12816-z
    DOI: 10.1038/s41467-019-12816-z
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    Cited by:

    1. Shintaro Mise & Akinobu Matsumoto & Keisuke Shimada & Toshiaki Hosaka & Masatomo Takahashi & Kazuya Ichihara & Hideyuki Shimizu & Chisa Shiraishi & Daisuke Saito & Mikita Suyama & Tomoharu Yasuda & To, 2022. "Kastor and Polluks polypeptides encoded by a single gene locus cooperatively regulate VDAC and spermatogenesis," Nature Communications, Nature, vol. 13(1), pages 1-17, December.
    2. Ara Lee & Gihyun Sung & Sanghee Shin & Song-Yi Lee & Jaehwan Sim & Truong Thi My Nhung & Tran Diem Nghi & Sang Ki Park & Ponnusamy Pon Sathieshkumar & Imkyeung Kang & Ji Young Mun & Jong-Seo Kim & Hyu, 2024. "OrthoID: profiling dynamic proteomes through time and space using mutually orthogonal chemical tools," Nature Communications, Nature, vol. 15(1), pages 1-14, December.

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