Organ structure and function can be affected by the presence of abnormal cells and there is increasing evidence that they can be removed by both cell intrinsic and cell-nonautonomous mechanisms. A cell intrinsic mechanism is exemplified by P53, which activates a transcriptional program that leads either to cell cycle arrest or to the elimination of the damaged cells through apoptosis (Kastenhuber and Lowe, 2017). Abnormal cells can also be removed by cell interactions in the process of cell competition, which recognizes and eliminate cells that are different from their neighbors. The classic example of cell competition is that of the Minute (M) mutations in Drosophila, which are loss of function mutations in ribosomal protein (Rp) genes (Marygold et al., 2007). Heterozygous Rp^+/- animals are viable, although they generally display a slower cell proliferation rate and developmental delay (Bridges and Morgan, 1923; Morata and Ripoll, 1975) but Rp^+/- cells undergo apoptosis when surrounded by wild-type Rp^+/+ cells (Morata and Ripoll, 1975; Simpson and Morata, 1981; Moreno et al., 2002; Li and Baker, 2007). Such non-autonomous cell competition also affects a number of other genotypes of cells in both Drosophila and in mammals (Amoyel and Bach, 2014; Clavería and Torres, 2016; Di Gregorio et al., 2016; Merino et al., 2016; Baker, 2017; Maruyama and Fujita, 2017; Nagata and Igaki, 2018). Interestingly, P53 is important for some examples of cell competition in mammals, but dispensable for the elimination of Rp^+/- cells in Drosophila (Baker et al., 2019). Although the potential roles of cell competition in development and in disease such as cancer are of considerable interest, little is yet known about molecular mechanisms of cell competition.

We, and others, identified Xrp1 as a key factor in the cell competition of Rp^+/- cells (Lee et al., 2016; Baillon et al., 2018; Lee et al., 2018). Xrp1 loss-of-function mutations allow Rp^+/- cells to survive when surrounded by wild-type (Rp^+/+) cells, preventing their elimination by cell competition (Baillon et al., 2018; Lee et al., 2018). Remarkably, Xrp1 is also required for the slow growth, reduced translation, and most of the gene expression changes shown by Rp^+/- cells, showing that Xrp1 is a central mediator of these effects of Rp gene mutations, none of which seems to depend simply on a reduced number of ribosomes (Lee et al., 2018). Xrp1 encodes a Basic region Leuzine-Zipper (bZIP) protein that also has an AT-hook domain, and was known earlier as a p53-target that is also implicated in P element transposition (Brodsky et al., 2004; Akdemir et al., 2007; Francis et al., 2016). Recently it has also been implicated in coordination of organ growth following local growth retardation (Boulan et al., 2019). bZip proteins typically bind DNA as homo- or heterodimers and many are evolutionarily conserved (Amoutzias et al., 2007; Reinke et al., 2013). Dimerization of Drosophila bZIP proteins has been analyzed in silico and in vitro (Fassler et al., 2002; Reinke et al., 2013). The bZIP protein encoded by the CG6272 gene was the only heterodimer partner of Xrp1 identified by in vitro FRET assays (Reinke et al., 2013). This heterodimer is also the sequence-specific DNA-binding component of a multiprotein complex that binds to the P-element Terminal Inverted Repeats leading to the naming of CG6272 as Inverted Repeat Binding Protein 18 (IRBP18) (Francis et al., 2016). Unusually, Xrp1 has been described as specific to the genus Drosophila (Akdemir et al., 2007), whereas irbp18 is well-conserved and belongs to the CAAT/Enhancer Binding Protein (C/EBP) superfamily of transcription factors, being most similar to human C/EBPγ (Ramji and Foka, 2002; Francis et al., 2016). IRBP18 can also heterodimerize with a second bZIP protein, dATF4 (Reinke et al., 2013). dATF4, encoded by the cryptocephal (crc) gene, controls molting and metamorphosis as a cofactor for the ecdysone receptor (Gauthier et al., 2012). Ecdysone is an important signal for imaginal disc growth (Delanoue et al., 2010; Jaszczak and Halme, 2016). In addition, dATF4 is neuroprotective in a model of Parkinsons Disease (Celardo et al., 2017), and regulates 4E-BP transcription downstream of GCN2 during nutrient stress (Kang et al., 2017; Malzer et al., 2018). dATF4 can heterodimerize with a further C/EBP protein, encoded by slow border cells (slbo) (Reinke et al., 2013). Thus, Xrp1 is potentially connected to a network of more conserved C/EBP-class bZip proteins, through IRBP18 (Figure 1A).

Figure 1

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Clone size data corresponding to Figure 1I.

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In the present study, we have analyzed the role of other bZip proteins connected to Xrp1 in Rp mutant cell competition. Out of the many possibilities, we were particularly interested in whether Xrp1 acts positively in cell competition as a heterodimer with IRBP18, potentially a Drosophila-specific complex, or behaves as a competitive inhibitor of the conserved stress response protein dATF4/Crc by sequestering IRBP18 away from it. Our results show that Xrp1 and irbp18 are both necessary for the slow-growth and cell competition of Rp^+/- cells, apparently independently of other IRBP18 partners, consistent with the first hypothesis. Additionally, we find that the upregulation of both Xrp1 and irbp18 in Rp^+/- cells depends on one another’s function, and that the DNA binding and dimerization domains are important for the function and regulation of these genes, further evidence of an auto-regulatory loop based on the Xrp1/IRBP18 heterodimer and necessary for cell competition. Finally, we identify rapidly-evolving Xrp1 homologs beyond Drosophila and suggest that divergent mammalian proteins might resemble Xrp1 functionally.

Heterozygous mutation of ribosomal protein genes lead to cell-autonomous, deleterious phenotypes in both flies and mammals and provide the classic example of a genotype that is eliminated from mosaics by competition (Morata and Ripoll, 1975; Oliver et al., 2004; Clavería and Torres, 2016). There is increasing interest in the potential roles of cell competition in mammalian development, cancer development, and in regenerative medicine (Clavería and Torres, 2016; Di Gregorio et al., 2016; Merino et al., 2016; Baker, 2017; Maruyama and Fujita, 2017; Ellis et al., 2019). A remarkable recent finding from Drosophila is that many of the phenotypic effects of mutating ribosomal protein genes are mediated by a putative transcription factor, Xrp1, rather than as a direct consequence of altered ribosome number (Lee et al., 2018). Accordingly, Xrp1 plays a key role in the elimination of Rp mutant cells by cell competition (Lee et al., 2016; Baillon et al., 2018; Lee et al., 2018). Xrp1 transcription and protein expression are elevated in Rp mutant cells, restricting translation, cellular growth rate, and the rate of organismal development, and enabling cell competition with nearby wild type cells (Lee et al., 2018). Xrp1 had previously been implicated in the DNA damage response downstream of p53 and in the transposition of P elements, and contributes to the pathology of a Drosophila model of Amyotrophic Lateral Sclerosis, as well as to the coordination of organ growth in flies with Rp gene knockdowns (Brodsky et al., 2004; Akdemir et al., 2007; Francis et al., 2016; Mallik et al., 2018; Boulan et al., 2019).

Xrp1 has been reported not to have homologs in other eukaryotes (Akdemir et al., 2007). This seems surprising given the highly conserved and fundamental roles of ribosomal proteins, and is a barrier to investigating the potential conservation of cell competition mechanisms and the roles of cell competition in mammals, for example in the development of cancer. Xrp1 binds to DNA as a heterodimer with Irbp18, the Drosophila homolog of the C/EBP protein family, which is a conserved protein (Akdemir et al., 2007; Francis et al., 2016) and co-purifies with it in cultured cells (Francis et al., 2016; Mallik et al., 2018). Irbp18 in turn heterodimerizes with the conserved protein dATF4, encoded by the crc gene in Drosophila (Reinke et al., 2013). This led us to investigate whether it is the Xrp1 heterodimer with the conserved Irbp18 protein that functions in Rp^+/- cells, and if so whether Xrp1/Irbp18 acts positively; alternatively, Xrp1 could act as a competitive inhibitor of Irbp18 function with its other partner, dAtf4/Crc, in which case Xrp1 could represent a Drosophila-specific regulator of a more conserved pathway.

Our data provide overwhelming genetic evidence that Xrp1 does function along with Irbp18. Like Xrp1 mutations, irbp18 mutation suppressed multiple effects of Rp mutations, including the elimination of Rp^+/- mutant cells by competitive apoptosis in the proximity of wild type cells and the reduced growth of Rp^+/- wing cells. Like Xrp1, irbp18 was also required for the prompt disappearance of Rp^-/- cell clones, which survived in the irbp18 mutant background. All these data were consistent with the model that Xrp1/Irbp18 heterodimers are the active species in Rp mutant cells and were inconsistent with the idea that Xrp1 might act as a competitive inhibitor of other Irbp18-containing species, as this would have predicted that Irb18 mutations would have had phenotypes opposite to those of Xrp1.

The phenotype of Crc knockdown is different from those of Xrp1 and irbp18 mutations. Whereas Xrp1 and irbp18 mutations enhance the growth and competitiveness of Rp^+/- cells, crc knockdown greatly diminished growth and survival of Rp^+/- cells. If Xrp1 was a Drosophila-specific competitive inhibitor of a conserved Crc/Irbp18 heterodimer that was required for growth, both irbp18 and crc mutants would show reduced growth, similar to Rp^+/- genotypes. In contrast to this, irbp18 mutants have little phenotype except in Rp^+/- genotypes, where their effects closely resemble those of Xrp1 mutants. Also, whereas crc knockdown strongly and cell-autonomously affected the growth of Rp^+/- cells, it had less effect on Rp^+/+ cells.

In addition to these findings in loss-of-function experiments, we also found that Xrp1 over-expression phenotypes depended on IRBP18, as would be expected if these proteins function together. We also found that Xrp1 over-expression at higher temperatures resulted in a still stronger eye phenotype where simultaneous irbp18 mutation restored normal eye size but did not completely restore eye morphology. This is consistent with some IRBP18-independent component to ectopic Xrp1 function that is either cold-sensitive or only apparent at the highest ectopic expression levels. There is not yet any evidence whether these over-expression effects are physiologically relevant.

Taken together, our findings suggest that the Xrp1/IRBP18 and Crc/IRBP18 heterodimers have independent and perhaps unrelated functions. Consistent with this, ectopic expression of IRBP18 had no phenotypic effect, suggesting that IRBP18 is normally made in excess, so that it is Xrp1 that is limiting for the growth inhibiting activities of the Xrp1/IRBP18 heterodimers, which do not impact IRBP18 availability sufficiently to affect Crc/Irbp18 functions.

As expected if Xrp1 functions in a heterodimer, the basic and Leucine Zipper domains were important for Xrp1 function, as was the AT hook. In over-expression assays only, there could be reduced activity of proteins deleted for any of these domains individually, but not of a truncation that precedes them all. When encoded from the endogenous locus, basic and AT-hook domains appeared absolutely required.

Mutual auto-regulation may be a significant feature of Xrp1 and IRBP18 function. As noted previously, the elevated Xrp1 and irbp18 transcription observed in Rp^+/- wing discs is dependent on Xrp1 function (Baillon et al., 2018; Lee et al., 2018)(Figure 3Q–R). Here we show that IRBP18 protein levels are also elevated in Rp^+/- cells in an Xrp1-dependent fashion, and that irbp18 is also required for the autoregulation. In principle, autoregulation could have been the major or indeed the only transcriptional function of the Xrp1/IRBP18 heterodimer, ie perhaps these proteins could control cell competition through other mechanisms once levels were sufficient. This cannot be completely correct, however, because Xrp1 was still substantially dependent on the irbp18 gene and on the Leucine Zipper and DNA binding domains when expressed using GAL4-driven transgenes that are independent of auto-regulation, so by-passing the requirement of auto-regulation does not relieve the requirements for heterodimerization and DNA binding domains. It is also worth noting that Xrp1 and irbp18 are both required to promptly eliminate Rp^-/- cells, where their expression does not require auto-regulation. Although implicating other transcriptional targets of Xrp1/IRBP18 in Rp^+/- and Rp^-/- cells, these studies do not rule out other functions besides transcription.

Previously it was thought that Xrp1 was restricted to the genus Drosophila, a surprising finding for a protein that has an important cellular function. We found, however, that Xrp1 genes have been under strong positive selection for rapid evolutionary change. Recurrent positive selection is often the sign of an evolutionary arms race, such as are often driven by host-pathogen interactions, sexual competition, or intra-genomic conflict (Valen, 1973; Sawyer et al. (2005); Clark et al. (2006); Elde and Malik (2009); Levine and Malik (2013); Enard et al., 2016). Possibly pathogens target Xrp1 to promote growth and survival of infected cells. It is interesting that Xrp1 is already documented to interact with one transposable element, the P element (Francis et al., 2016). However, none of these scenarios for positive selection, or indeed additional possibilities, can yet be ruled out.

Rapid divergence makes homology difficult to detect, and accordingly we now identify divergent Xrp1 homologs in other Dipteran insects that have not previously been annotated because their sequence similarities are restricted to the key DNA-binding portion of the protein, and to a more amino-terminal Xrp1-homology domain. The failure to identify still more distant homologs might be genuine, or might reflect further divergence beyond our ability to recognize homology. Mammals do contain other members of the C/EBP protein family without identified Drosophila homologs, and we show that DDIT3 (aka CHOP and C/EBP-Z) can generate a similar phenotype to Xrp1 when expressed in Drosophila. Interestingly C/EBP-α, one of the mammalian proteins more related to Irbp18, has been implicated in a cell competition-like phenomenon, the elimination of cells from the multipotent hematopoietic stem cell niche following irradiation (Fleenor et al., 2015).

All data generated or analysed during this study are included in the manuscript and supporting files.

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Author details

1. Jorge Blanco

   Department of Genetics, Albert Einstein College of Medicine, New York, United States

   Present address

   Department of Ecology, Evolution and Behavior, University of Minnesota, St. Paul, USA

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing—original draft, Writing—review and editing

   Competing interests

   No competing interests declared

2. Jacob C Cooper

   School of Biological Sciences, University of Utah, Salt Lake City, United States

   Contribution

   Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Writing—review and editing

   Competing interests

   No competing interests declared

3. Nicholas E Baker

   Department of Genetics, Albert Einstein College of Medicine, New York, United States

   Contribution

   Conceptualization, Data curation, Funding acquisition, Investigation, Project administration, Writing—review and editing

   For correspondence

   nicholas.baker@einstein.yu.edu

   Competing interests

   No competing interests declared

   "This ORCID iD identifies the author of this article:" 0000-0002-4250-3488

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