The transcription factor Xrp1 orchestrates both reduced translation and cell competition upon defective ribosome assembly or function

Abstract

Ribosomal Protein (Rp) gene haploinsufficiency affects overall translation rate, leads to cell elimination by competition with wild type cells in mosaic tissues, and sometimes leads to accumulation of protein aggregates. The changes in ribosomal subunit levels observed are not sufficient for these effects, which all depend on the AT-hook, bZip domain protein Xrp1. In Rp+/− cells, Xrp1 reduced global translation through PERK-dependent phosphorylation of eIF2α. eIF2α phosphorylation was sufficient to reduce translation in, and also enable cell competition of, otherwise wild type cells. Unexpectedly, however, many other defects reducing ribosome biogenesis or function (depletion of TAF1B, eIF2, eIF4G, eIF6, eEF2, eEF1α1, or eIF5A), also increased eIF2α phosphorylation and enabled cell competition. In all cases this was through the Xrp1 expression that was induced, placing Xrp1 as the downstream instigator of cell competition that also contributed to overall translation deficits. In the absence of Xrp1, translation differences between cells were not themselves sufficient to trigger cell competition. Thus, Xrp1, which is shown here to be a sequence-specific transcription factor, is the master regulator that triggers cell competition and other consequences of multiple ribosomal stresses.

Xrp1 and Irbp18 trigger a feed-forward loop of proteotoxic stress to induce the loser status

“…Knockdown of Xrp1 or Irbp18 rescues proteotoxic stress in RpS3/+ cells, suggesting that this feed-forward loop is essential for build-up of proteotoxic stress and to reduce the competitiveness of Rp/+ cells. We note that during the revision of this manuscript two other independent studies have reported relevant and complementary findings [ 46 , 47 ]. Nrf2 is also activated by proteotoxic stress and contributes to this feedback loop, either independently of p-eIF2α (as illustrated in Fig 6G ), or downstream of p-eIF2α.…”

Cell competition is driven by Xrp1-mediated phosphorylation of eukaryotic initiation factor 2α

“…Importantly, our data show that eIF2α phosphorylation is also required for the induction of loser's death. Similarly, recent studies have shown that M/+ cells experience proteotoxic stress and thus induce phosphorylation of eIF2α, which acts as a driver of M/+ cell competition [30][31][32][33]. Whether the global inhibition of protein synthesis or other downstream event(s) of eIF2α phosphorylation such as upregulation of UPR-activating transcription factor ATF4 is linked to their apoptosis is an outstanding important question.…”

“…These observations suggest that Xrp1 acts both upstream and downstream of the PERK-eIF2α axis in a positive feedback loop. The upstream Xrp1 may activate the PERK-eIF2α axis via upregulation of PERK expression [ 33 ]. Alternatively, Xrp1 upregulation may cause ER stress, which induces PERK activation.…”