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

• Published in: Nature communications Vol. 12; no. 1; pp. 508 - 15
• Main Authors: Cao, Xiongwen, Khitun, Alexandra, Luo, Yang, Na, Zhenkun, Phoodokmai, Thitima, Sappakhaw, Khomkrit, Olatunji, Elizabeth, Uttamapinant, Chayasith, Slavoff, Sarah A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 21.01.2021; Nature Publishing Group; Nature Portfolio
• Subjects: 1-Phosphatidylinositol 3-kinase; 38; 45; 631/208/726/1912; 631/45/475; 631/45/611; 631/80/86; AKT protein; Alternative Splicing; Amino Acid Sequence; Base Sequence; Biological Transport; Cell Membrane - metabolism; Cell size; Down-Regulation; Endoplasmic reticulum; Endoplasmic Reticulum - metabolism; HEK293 Cells; Humanities and Social Sciences; Humans; Membrane Proteins - genetics; Membrane Proteins - metabolism; Membranes; Molecular modelling; multidisciplinary; Mutation; Open reading frames; Phosphatidylinositol 3-Kinases - metabolism; Phosphatidylinositol 4,5-diphosphate; Phosphatidylinositol 4,5-Diphosphate - metabolism; Phosphoserine; Polypeptides; Protein Binding; Proteins; Proto-Oncogene Proteins c-akt - metabolism; Ribosomal Proteins - genetics; Ribosomal Proteins - metabolism; Science; Science (multidisciplinary); Signal Transduction; Signaling; TOR protein; TOR Serine-Threonine Kinases - metabolism; Transcription
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-20841-6

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)P 2 ) precursor phosphatidylinositol from the endoplasmic reticulum to the plasma membrane. Knock-out of alt-RPL36 increases plasma membrane PI(4,5)P 2 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. Many alternative ORFs are co-encoded with characterized proteins, but their function is often not understood. Here, the authors discover that ribosomal protein L36 is co-encoded with alternative protein, which they identify as an upstream regulator of PI3K-AKT-mTOR signaling.