| First Author | Ding P | Year | 2022 |
| Journal | Cell Rep | Volume | 39 |
| Issue | 9 | Pages | 110851 |
| PubMed ID | 35649359 | Mgi Jnum | J:326469 |
| Mgi Id | MGI:7311488 | Doi | 10.1016/j.celrep.2022.110851 |
| Citation | Ding P, et al. (2022) Intracellular complement C5a/C5aR1 stabilizes beta-catenin to promote colorectal tumorigenesis. Cell Rep 39(9):110851 |
| abstractText | Complement is operative in not only the extracellular but also the intracellular milieu. However, little is known about the role of complement activation inside tumor cells. Here, we report that intracellular C5 is cleaved by cathepsin D (CTSD) to produce C5a in lysosomes and endosomes of colonic cancer cells. After stimulation by C5a, intracellular C5aR1 assembles a complex with KCTD5/cullin3/Roc-1 and beta-catenin to promote the switch of polyubiquitination of beta-catenin from K48 to K63, which enhances beta-catenin stability. Genetic loss or pharmacological blockade of C5aR1 dramatically impedes colorectal tumorigenesis at least by destabilizing beta-catenin. In human colorectal cancer specimens, high levels of C5aR1, C5a, and CTSD are closely correlated with elevated beta-catenin levels and a poor prognosis. Importantly, intracellular C5a/C5aR1-mediated beta-catenin stabilization is also observed ubiquitously in other cell types. Collectively, we identify a machinery for beta-catenin activation and provide a potential target for tumor prevention and treatment. |
