Biology subjects

Kiparaki, M.

Publications and source records attributed to Kiparaki, M..

3 recordsLinked to original sources

bioRxiv2025

RpS12-mediated induction of the Xrp1short isoform links ribosomal protein mutations to cell competition

Cell competition, a universal yet enigmatic phenomenon, eliminates less-fit cells via interactions with their neighbors. It was originally described in Drosophila mosaics, where heterozygous ribosomal protein (Rp+/-) mutant cells are eliminated by wild-type neighbors. The transcription factor Xrp1 mediates most of the Rp+/- -associated phenotypes, including reduced competitiveness and translation. Although RpS12 is required for Xrp1 induction in Rp+/- cells, the mechanism remained unresolved. We demonstrate that RpS12, via alternative splicing, induces the Xrp1 short (Xrp1short) isoform expression in Rp+/- cells, which is both necessary and sufficient for their elimination. Strikingly, RpS12 overexpression in wild-type cells is sufficient to induce Xrp1short expression and confer a "loser" phenotype. While Xrp1long isoform is not required in Rp+/- cells, expression of either Xrp1 isoform is sufficient to promote the loser status in wild-type cells. We further identify Syncrip, an RNA-binding protein reduced in Rp+/- cells, as a critical Xrp1 suppressor; its depletion in wild-type cells activates Xrp1-dependent competition. Our findings establish RpS12s specialized function in Xrp1short promotion, not proteotoxic stress, as the primary driver in Rp+/- cells, providing new perspectives that challenge and refine prevailing models. Our work contributes in long-standing questions about ribosomal protein-linked fitness surveillance and provides insights into ribosomopathy pathologies.

developmental biology↗

bioRxiv2021

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

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 eIF2. eIF2 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, eEF11, or eIF5A), also increased eIF2 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.

developmental biology↗

bioRxiv2021

Cell competition removes segmental aneuploid cells from Drosophila imaginal disc-derived tissues based on ribosomal protein gene dose

Aneuploidy causes birth defects and miscarriages, occurs in nearly all cancers, and is a hallmark of aging. Individual aneuploid cells can be eliminated from developing tissues by unknown mechanisms. Cells with ribosomal protein (Rp) gene mutations are also eliminated, by cell competition with normal cells. Because Rp genes are spread across the genome, their copy number is a marker for chromosome aberrations. Elimination of imaginal disc cells with irradiation-induced genome damage often required cell competition genes. When defined chromosome regions were deleted, segmentally-aneuploid cells were eliminated by the RpS12-Xrp1 cell competition pathway in an apoptosis- dependent manner when they differed from neighboring cells in Rp gene dose. Cells with normal doses of the Rp (and eIF2{gamma}) genes survived and differentiated adult tissues. Thus, cell competition, triggered by differences in Rp gene dose between cells, is a significant mechanism for the elimination of aneuploid somatic cells, likely to contribute to preventing cancer.

genetics↗