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

Ribosomal Protein (Rp) gene haploinsufficiency affects translation rate, can lead to protein aggregation, and causes cell elimination by competition with wild type cells in mosaic tissues. We find that the modest changes in ribosomal subunit levels observed were insufficient for these effects, which all depended on the AT-hook, bZip domain protein Xrp1. Xrp1 reduced global translation through PERK-dependent phosphorylation of eIF2 alpha. eIF2 alpha phosphorylation was itself sufficient to enable cell competition of otherwise wild type cells, but through Xrp1 expression, not as the downstream effector of Xrp1. Unexpectedly, many other defects reducing ribosome biogenesis or function (depletion of TAF1B, eIF2, eIF4G, eIF6, eEF2, eEF1 alpha 1, or eIF5A), also increased eIF2 alpha phosphorylation and enabled cell competition. This was also through the Xrp1 expression that was induced in these depletions. In the absence of Xrp1, translation differences between cells were not themselves sufficient to trigger cell competition. Xrp1 is shown here to be a sequence-specific transcription factor that regulates transposable elements as well as single-copy genes. Thus, Xrp1 is the master regulator that triggers multiple consequences of ribosomal stresses and is the key instigator of cell competition.

Automated summary

Haploinsufficiency of ribosomal protein genes affects translation rate, leading to protein aggregation and cell elimination by competition with wild type cells. This study identifies Xrp1 as a key regulator that reduces global translation through PERK-dependent phosphorylation of eIF2 alpha, enabling cell competition. Xrp1 is also found to be induced in other defects affecting ribosome biogenesis or function, further promoting cell competition.