Combinatorial post-translational modification reprogramming of the endomembrane system in colorectal cancer

The endomembrane system plays a pivotal role in protein synthesis, trafficking, and degradation, and has been implicated in colorectal cancer (CRC) progression. Post-translational modifications (PTMs) regulate endomembrane-associated proteins, but a comprehensive understanding of how multiple PTMs collectively impact the endomembrane system in CRC remains limited. This study aimed to systematically map multi-PTM landscapes in CRC and uncover potential regulatory nodes within the endomembrane system.

We developed a multi-PTM proteomic atlas of CRC by profiling phosphorylation, ubiquitination, and malonylation in paired tumor and adjacent normal tissues (n=8 pairs). The PTM datasets were derived from an in-house CRC cohort. Differentially modified proteins (DMPs) were annotated, structurally mapped, and integrated into protein-protein interaction (PPI) networks to explore regulatory patterns associated with the endomembrane system.

We identified extensive PTM alterations in CRC, including 84 phosphorylation, 123 ubiquitination, and 16 malonylation sites. LMNB1 and LMNB2 emerged as combined PTM proteins, with alterations in phosphorylation, ubiquitination, and malonylation potentially influencing nuclear pore function, chromatin organization, and the activation of the WNT/β-catenin pathway. These findings underscore LMNB1/LMNB2 may play a potential role in the regulation of the CRC endomembrane system, offering potential targets for further mechanistic and therapeutic studies.

This study provides a multi-PTM resource delineating the CRC endomembrane system. The identified modification hotspots, such as multi-modified LMNB1/2, offer promising molecular candidates for further mechanistic studies of endomembrane dysregulation in CRC.