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Multi-omics Analysis Sheds Light on the Extracellular Role of PCMT1
Jie Wang1,2,3, Jia Xia4, Juncheng Su5
1Department of Biochemistry and Molecular Cell Biology, Shanghai Key Laboratory for Tumor Microenvironment and Inflammation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, P.R. China.
Abstract:
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 o-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 Pcmt1 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.
Insights
Protein damage from isoaspartate (isoD) accumulation is linked to aging and disease. The study reveals protein repair enzyme PCMT1 (protein-l-isoaspartate O-methyltransferase) has crucial roles in non-neural tissues and unexpectedly in extracellular functions.
Area of Science:
- Biochemistry
- Molecular Biology
- Proteomics
Background:
- Protein damage, including isoaspartate (isoD) modification, accumulates with age and disease.
- The enzyme protein-l-isoaspartate O-methyltransferase (PCMT1) repairs isoD residues, preventing aberrant protein function.
- PCMT1's function in non-neural tissues is largely unknown.
Purpose of the Study:
- To investigate the role of PCMT1 in non-neural tissues using a Pcmt1 knockout mouse model.
- To identify proteins and genes affected by the absence or overexpression of PCMT1.
- To explore the genome-proteome correlations and extracellular functions of PCMT1.
Main Methods:
- Utilized isoD-proteomics, global proteomics, and transcriptomics in Pcmt1 knockout (KO) and wild-type (WT) mice.
- Analyzed gene and protein expression changes in various KO tissues.
- Performed proteomic analysis on PCMT1-overexpressing cells.
Main Results:
- Significant gene and protein alterations were observed in KO tissues, particularly in extracellular and membrane-related categories.
- IsoD-modified proteins, primarily long-lived ones, increased in KO tissues.
- PCMT1 interacts with proteins involved in extracellular and membrane functions, suggesting a novel extracellular role.
Conclusions:
- PCMT1 plays vital roles in maintaining protein integrity in both physiological and stress conditions across various tissues.
- PCMT1 exhibits both shared and tissue-specific functions.
- This study uncovers a previously unrecognized extracellular function for PCMT1.
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