RT Journal Article
SR Electronic
T1 Noncanonical altPIDD1 protein: unveiling the true major translational output of the <em>PIDD1</em> gene
JF Life Science Alliance
JO Life Sci. Alliance
FD Life Science Alliance LLC
SP e202402910
DO 10.26508/lsa.202402910
VO 8
IS 2
A1 Comtois, Frédérick
A1 Jacques, Jean-François
A1 Métayer, Lenna
A1 Ouedraogo, Wend Yam DD
A1 Ouangraoua, Aïda
A1 Denault, Jean-Bernard
A1 Roucou, Xavier
YR 2025
UL https://www.life-science-alliance.org/content/8/2/e202402910.abstract
AB Proteogenomics has enabled the detection of novel proteins encoded in noncanonical or alternative open reading frames (altORFs) in genes already coding a reference protein. Reanalysis of proteomic and ribo-seq data revealed that the p53-induced death domain-containing protein (or PIDD1) gene encodes a second 171 amino acid protein, altPIDD1, in addition to the known 910-amino acid-long PIDD1 protein. The two ORFs overlap almost completely, and the translation initiation site of altPIDD1 is located upstream of PIDD1. AltPIDD1 has more translational and protein level evidence than PIDD1 across various cell lines and tissues. In HEK293 cells, the altPIDD1 to PIDD1 ratio is 40 to 1, as measured with isotope-labeled (heavy) peptides and targeted proteomics. AltPIDD1 localizes to cytoskeletal structures labeled with phalloidin and interacts with cytoskeletal proteins. Unlike most noncanonical proteins, altPIDD1 is not evolutionarily young but emerged in placental mammals. Overall, we identify PIDD1 as a dual-coding gene, with altPIDD1, not the annotated protein, being the primary product of translation.