Emerging Roles of the Unique Molecular Chaperone Cosmc in the Regulation of Health and Disease

Abstract

The core-1 β1-3galactosyltransferase-specific chaperone 1 (Cosmc) is a unique molecular chaperone of core-1 β1-3galactosyltransferase(C1GALT1), which typically functions inside the endoplasmic reticulum (ER). Cosmc helps C1GALT1 to fold correctly and maintain activity. It also participates in the synthesis of the T antigen, O-glycan, together with C1GALT1. Cosmc is a multifaceted molecule with a wide range of roles and functions. It involves platelet production and the regulation of immune cell function. Besides that, the loss of function of Cosmc also facilitates the development of several diseases, such as inflammation diseases, immune-mediated diseases, and cancer. It suggests that Cosmc is a critical control point in diseases and that it should be regarded as a potential target for oncotherapy. It is essential to fully comprehend Cosmc's roles, as they may provide critical information about its involvement in disease development and pathogenesis. In this review, we summarize the recent progress in understanding the role of Cosmc in normal development and diseases.

Keywords: C1GALT1; Cosmc; O-glycosylation; Tn antigen; chaperonin.

Figure 1

Schematic diagram of the biosynthesis of O-glycan. O-glycosylation is normally initiated in the Golgi apparatus. With the assistance of the molecular chaperone Cosmc, C1GALT1 adds Gal from UDP-Gal to the Tn antigen to form the T antigen, which is extended by adding other sugars to produce normal O-glycans. Without Cosmc, the function of C1GALT1 would be lost, resulting in the generation of Tn and/or Sialyl Tn antigen, which is usually associated with the molecular mechanisms of the development of various diseases or tumors.

Figure 2

Model of Cosmc structure. The N-terminal domain of Cosmc (dark blue) is responsible for interacting with C1GALT1 (red peptide) for chaperone function, and the C-terminal domain (light blue) mediates oligomerization and Zn²⁺ binding.

Figure 3

Working model for Cosmc function. Human Cosmc is located in the ER, where it interacts with the activated C1GALT1. Activated C1GALT1 is inserted into the Golgi apparatus and is involved in the synthesis of core-1 O-glycans (T antigens). When Cosmc is mutated and dysfunctional, misfolded C1GALT1 aggregates in the endoplasmic reticulum and is retrotranslocated from the endoplasmic reticulum to the cytosol, where it is ubiquitinated and degraded by the proteasomal machinery.

Figure 4

The colon has a two-layered mucus system; the outer layer is infiltrated by intestinal bacteria, and the inner layer is unaffected by bacteria and physically separates them from the epithelium. The lack of defects in this inner MUC2 mucin, which is the main mucus component of the intestine, disrupts the protective properties of the inner colonic mucus layer, allowing direct contact between bacteria and epithelial cells to cause inflammation and bleeding.