Alt-RPL36 downregulates the PI3K-AKT-mTOR signaling pathway by interacting with TMEM24

Xiongwen Cao, Alexandra Khitun, Yang Luo, Zhenkun Na, Thitima Phoodokmai, Khomkrit Sappakhaw, Elizabeth Olatunji, Chayasith Uttamapinant and Sarah A. Slavoff ()
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Xiongwen Cao: Yale University
Alexandra Khitun: Yale University
Yang Luo: Yale University
Zhenkun Na: Yale University
Thitima Phoodokmai: Vidyasirimedhi Institute of Science and Technology (VISTEC)
Khomkrit Sappakhaw: Vidyasirimedhi Institute of Science and Technology (VISTEC)
Elizabeth Olatunji: Yale University
Chayasith Uttamapinant: Vidyasirimedhi Institute of Science and Technology (VISTEC)
Sarah A. Slavoff: Yale University

Nature Communications, 2021, vol. 12, issue 1, 1-15

Abstract: Abstract Thousands of human small and alternative open reading frames (smORFs and alt-ORFs, respectively) have recently been annotated. Many alt-ORFs are co-encoded with canonical proteins in multicistronic configurations, but few of their functions are known. Here, we report the detection of alt-RPL36, a protein co-encoded with human RPL36. Alt-RPL36 partially localizes to the endoplasmic reticulum, where it interacts with TMEM24, which transports the phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) precursor phosphatidylinositol from the endoplasmic reticulum to the plasma membrane. Knock-out of alt-RPL36 increases plasma membrane PI(4,5)P2 levels, upregulates PI3K-AKT-mTOR signaling, and increases cell size. Alt-RPL36 contains four phosphoserine residues, point mutations of which abolish interaction with TMEM24 and, consequently, alt-RPL36 effects on PI3K signaling and cell size. These results implicate alt-RPL36 as an upstream regulator of PI3K-AKT-mTOR signaling. More broadly, the RPL36 transcript encodes two sequence-independent polypeptides that co-regulate translation via different molecular mechanisms, expanding our knowledge of multicistronic human gene functions.

Date: 2021
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DOI: 10.1038/s41467-020-20841-6

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