Multi-omics Analysis Sheds Light on the Extracellular Role of PCMT1

Proteins are constantly damaged by intracellular and extracellular factors, particularly under stress conditions, leading to an accumulation of modified proteins such as isoaspartate (isoD), which is linked to aging and various diseases. The repair enzyme PCMT1 (protein-l-isoaspartate <i>o</i>-methyltransferase) specifically restores isoD residues to aspartate, preventing abnormal protein functions. Despite its importance, its role in non-neural tissues remains underexplored. This study employed isoD-proteomics, global proteomics, and transcriptomics on <i>Pcmt1</i> knockout (KO) and wild-type (WT) mice, revealing significant gene and protein changes in various KO tissues, enriched in extracellular and membrane-related categories, highlighting genome-proteome correlations. IsoD-carrying proteins were increased in KO tissues, predominantly consisting of long-lived proteins. Additionally, the proteomic analysis of PCMT1-overexpressing cells identified interacting proteins mainly in extracellular and membrane-related categories. These findings revealed both tissue-specific and shared roles of PCMT1, emphasizing its importance in maintaining protein integrity under physiological and stress conditions while also uncovering an unexpected extracellular function of PCMT1.