Drosophila RpS12 controls translation, growth, and cell competition through Xrp1

Abstract

Whereas complete loss of Rp function is generally lethal, most heterozygous Rp mutants grow more slowly and are subject to competitive loss from mosaics tissues that also contain wild type cells. The rpS12 gene has a special role in the cell competition of other Ribosomal Protein (Rp) mutant cells in Drosophila. Elimination by cell competition is promoted by higher RpS12 levels and prevented by a specific rpS12 mis-sense mutation, identifying RpS12 as a key effector of cell competition due to mutations in other Rp genes. Here we show that RpS12 is also required for other aspects of Rp mutant phenotypes, including hundreds of gene expression changes that occur in ‘Minute’ Rp heterozygous wing imaginal discs, overall translation rate, and the overall rate of organismal development, all through the bZip protein Xrp1 that is one of the RpS12-regulated genes. Our findings outline the regulatory response to mutations affecting essential Rp genes that controls overall translation, growth, and cell competition, and which may contribute to cancer and other diseases.

Mechanisms underlying the cooperation between loss of epithelial polarity and Notch signaling during neoplastic growth in Drosophila

“…Finally, we show that similarly to what was previously described for Ras signaling (Atkins et al, 2016), the cooperation between Notch signaling and polarity loss is controlled by a “tumor transcriptional network” centered around the AP-1/Stat/Yki transcription factors, and including the critical bZIP factors Pdp1 and CEPBG (CG6272/Irbp18). But our analysis uncovered a previously unreported role for the cell competition regulator, and Irbp18 binding partner Xrp1 (Baillon et al, 2018; Blanco et al, 2020; Boulan et al, 2019; Ji et al, 2019), raising the interesting prospect that neoplastic growth could be mediated at least in part, by co-opting cell competition.…”

“…This would align with the NS specific GO categories “cellular response to gamma radiation” (GO:0071480), and “DNA damage checkpoints” (GO:0031571/0007095). Indeed, Xrp1 has recently been linked to cell competition and shown to control the expression of a subset of genes activated in response to Ribosomal protein haplo-insufficiency including Ets21C , upd3 , or ilp8 in developing wing discs (Baillon et al, 2018; Boulan et al, 2019; Ji et al, 2019). Strikingly, we observed a very strong overlap between the Xrp1 transcriptional program (Supplemental Table S16) and the genes activated in NS (60 out of the 171 Xrp1 positively regulated genes are also upregulated in NS; hypergeometric test, p=4.71 10e-21), while a much more modest overlap could be observed with N or S (overlap of 17 and 33 with p values of 1.12 10e-3 and 1.56 10e-8 respectively).…”

“…CG6272/Irbp18 also interacts with Xrp1, and the heterodimer has been implicated in DNA repair (Akdemir et al, 2007; Francis et al, 2016). We thus propose that the Irbp18/Xrp1 dimer is activated in NS and is required to facilitate DNA repair and ensure genomic stability to prevent catastrophic genotoxic effect upon the combined cellular stresses of S and replication stress of N. Recently, Xrp1 together with its binding partner CG6272/Irbp18 (but not Atf4) has been shown to mediate a loser status in ribosomal genes deficient cells, through the implementation of a specific transcriptional program (Baillon et al, 2018; Blanco et al, 2020; Ji et al, 2019). This “loser state” promoter role of Xrp1/Irbp18 is however in conflict with our observation that Xrp1 is strongly upregulated in NS overgrowing discs, and that Xrp1 and Irbp18 are required for the overgrowth and invasive capacities of NS neoplastic cells.…”

“…Xrp1 target genes. Xrp1 regulated genes identified in Ji et al (2019) (positively and negatively) and in Baillon et al (2018). In bold are highlighted genes found in both studies.…”

“…We further provide evidence that this Notch redirection is not mediated by new genomic binding regions for Su(H), but relies on the cooperation with Su(H) of a combination of transcription factors, such as basic leucine zipper (bZIP), whose activity is triggered in response to JNK signaling during polarity loss, extending earlier reports on the cooperation between oncogenic Ras and polarity loss (Atkins et al, 2016; Külshammer et al, 2015; Uhlirova and Bohmann, 2006). Our work highlights in particular the role of the stress response CEBPG homologue CG6272/Irbp18 and of its partner Xrp1, key factors in mediating the loser fate during cell competition (Baillon et al, 2018; Blanco et al, 2020; Ji et al, 2019), suggesting that cellular competition, or parts of the cellular competition program, are co-opted during neoplastic growth.…”