ACKR3 induces the perturbation of rRNA biogenesis: a novel mechanism of colorectal tumorigenesis

Atypical chemokine receptor 3 (ACKR3), previously known as C-X-C chemokine receptor type 7 (CXCR7), has emerged as a key player in several biologic processes. Its atypical "intercepting receptor" signaling properties have established ACKR3 as the main regulator in pathophysiological processes in many diseases. However, much less is known the underlying mechanisms of ACKR3 in promoting tumorigenesis. We found, in both human and animal model, that activation of ACKR3 promotes colorectal tumorigenesis through the NOLC1-induced perturbations of rRNA biogenesis. As compared with adjacent non-neoplastic tissue, human colonic cancer tissues demonstrated higher expression of ACKR3, and high ACKR3 expression was associated with increased severity of colonic cancer. Villin-ACKR3 transgenic mice demonstrated the characteristics of ACKR3-induced colorectal cancer, showing the nuclear {beta}-arrestin-1-activated perturbation of rRNA biogenesis. Activation of ACKR3 induced nuclear translocation of {beta}-arrestin-1 ({beta}-arr1), leading to the interaction of {beta}-arr1 with nucleolar and coiled-body phosphoprotein 1 (NOLC1). As the highly phosphorylated protein in the nucleolus, NOLC1 further interacted with Fibrillarin, a highly conserved nucleolar methyltransferase responsible for ribosomal RNA methylation, leading to the increase of methylation in Histone H2A, resulting in the promotion of rRNA transcription of ribosome biogenesis. Conclusion: ACKR3 promotes colorectal tumorigenesis through the perturbation of rRNA biogenesis by nuclear {beta}-arr1-induced interaction of NOLC1 with Fibrillarin. HIGH LIGHTSO_LIACKR3 is an atypical G protein-coupled receptor (GPCR) C_LIO_LIACKR3 promotes colorectal tumorigenesis C_LIO_LIACKR3 induces nuclear translocation of {beta}-arr1 C_LIO_LINuclear {beta}-arr1 interacts with NOLC1 to activate Fibrillarin C_LIO_LIInteraction of NOLC1 to Fibrillarin leads to perturbation of rRNA biogenesis C_LI