| Summary: | <i>C</i>-Mannosylation is a post-translational modification of proteins in the endoplasmic reticulum. Monomeric α-mannose is attached to specific Trp residues at the first Trp in the Trp-x-x-Trp/Cys (W-x-x-W/C) motif of substrate proteins, by the action of <i>C</i>-mannosyltransferases, <i>DPY19</i>-related gene products. The acceptor substrate proteins are included in the thrombospondin type I repeat (TSR) superfamily, cytokine receptor type I family, and others. Previous studies demonstrated that <i>C</i>-mannosylation plays critical roles in the folding, sorting, and/or secretion of substrate proteins. A <i>C</i>-mannosylation-defective gene mutation was identified in humans as the disease-associated variant affecting a <i>C</i>-mannosylation motif of W-x-x-W of ADAMTSL1, which suggests the involvement of defects in protein <i>C</i>-mannosylation in human diseases such as developmental glaucoma, myopia, and/or retinal defects. On the other hand, monomeric <i>C</i>-mannosyl Trp (<i>C</i>-Man-Trp), a deduced degradation product of <i>C</i>-mannosylated proteins, occurs in cells and extracellular fluids. Several studies showed that the level of <i>C</i>-Man-Trp is upregulated in blood of patients with renal dysfunction, suggesting that the metabolism of <i>C</i>-Man-Trp may be involved in human kidney diseases. Together, protein <i>C</i>-mannosylation is considered to play important roles in the biosynthesis and functions of substrate proteins, and the altered regulation of protein <i>C</i>-manosylation may be involved in the pathophysiology of human diseases. In this review, we consider the biochemical and biomedical knowledge of protein <i>C</i>-mannosylation and <i>C</i>-Man-Trp, and introduce recent studies concerning their significance in biology and medicine.
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