{Reference Type}: Journal Article
{Title}: Regulation of non-canonical proteins from diverse origins through the nonsense-mediated mRNA decay pathway.
{Author}: Periasamy P;Joseph C;Campos A;Rajandran S;Batho C;Hudson JE;Sivakumaran H;Kore H;Datta K;Yeong J;Gowda H;
{Journal}: Proteomics
{Volume}: 0
{Issue}: 0
{Year}: 2024 Feb 13
{Factor}: 5.393
{DOI}: 10.1002/pmic.202300361
{Abstract}: Immunotherapy harnesses neoantigens encoded within the human genome, but their therapeutic potential is hampered by low expression, which may be controlled by the nonsense-mediated mRNA decay (NMD) pathway. This study investigates the impact of UPF1-knockdown on the expression of non-canonical/mutant proteins, employing proteogenomic to explore UPF1 role within the NMD pathway. Additionally, we conducted a comprehensive pan-cancer analysis of UPF1 expression and evaluated UPF1 expression in Triple-Negative Breast Cancer (TNBC) tissue in-vivo. Our findings reveal that UPF1-knockdown leads to increased translation of non-canonical/mutant proteins, particularly those originating from retained-introns, pseudogenes, long non-coding RNAs, and unannotated transcript biotypes. Moreover, our analysis demonstrates elevated UPF1 expression in various cancer types, with notably heightened protein levels in patient-derived TNBC tumors compared to adjacent tissues. This study elucidates UPF1 role in mitigating transcriptional noise by degrading transcripts encoding non-canonical/mutant proteins. Targeting this mechanism may reveal a new spectrum of neoantigens accessible to the antigen presentation pathway. Our novel findings provide a strong foundation for the development of therapeutic strategies aimed at targeting UPF1 or modulating the NMD pathway.