Clonal expansions can remodel entire tissues even when they appear normal, but what mechanisms drive this? And how do these processes differ from tumorigenesis? Out @Nature, we identify distinct TNF programs during tumor evolution. 🧵.

The summer of defenses continues, huge congratulations Dr. Yigit for a superbly delivered talk and an excellent defense!

The very first PhD graduate of our lab! Great science, fantastic presentation and expertly defended. Huge congratulations on this well-earned milestone Dr. Duré!

Collectively, our study identifies a new link between eIF2A and ribosome-associated quality control (RQC), implies that eIF2A promotes translation fidelity by tuning 40S ribosome rescue under stress and warrants further investigations into the role of RQC in tumorigenesis. 6/x

Finally, in lung SCC patient data, we find increased K214-RPS3 ubiquitination, the very site targeted during RQC. RNF10 and eIF2A mRNA levels both correlate with shorter overall survival, pointing to a potential link between RQC induction and tumor progression. 5/x

G3BP1–USP10 complexes rescue stalled 40S from degradation. Using dynamic SILAC in mouse and human cells, we find eIF2A KO cells have reduced 40S turnover under stress, indicating that eIF2A tunes USP10-mediated 40S rescue under stress. 4/x

Consistent with recent Ribo-seq, our 40S TCP-seq analyses reveal only a minimal role in initiation. Rather, eIF2A loss causes a marked reduction in RPS3 ubiquitination upon stalling. We demonstrate that eIF2A antagonizes USP10-mediated deubiquitination of stalled 40S subunits. 3/

Led by the skilled @mervisyigit, we performed TurboID proximity biotinylation in both homeostatic and stressed cells. Zooming into 40S interactions, we locate eIF2A near the mRNA entry channel and uncover strong interactions with G3BP1-USP10 complexes and RPS2 and RPS3. 2/x

Identified in the 1970s, the precise molecular function of the alternative initiation factor eIF2A has remained unclear. Here, we map its interactome and uncover a surprising role in ribosome-associated quality control (RQC) upon ribosome stalling. 1/x.

RT @Nature: Nature research paper: Taurine from tumour niche drives glycolysis to promote leukaemogenesis.

RT @MariaPAlcolea: You won’t want to miss us in stunning Malta!🌴Get ready to be inspired~STEM CELLS & CANCER conference. INCREDIBLE LINE-U….

The former GRC Stem Cells & Cancer has found its new home in paradise - amazing meeting ahead!.

Our study establishes a framework for dissecting the functional significance of the dark proteome, uncovers a second Rpl41 gene critical for ribosome function and suggests pseudogenes as potential reservoirs of functional microproteins that expand the cellular proteome. 9/9.

Our findings suggest that Gm10076 acts as a second Rpl41 source, explaining mild effects of Rpl41 loss. Knockdown Rpl41 in Gm10076 mutants fully halted proliferation. Thus, although RPL41 has been considered non-essential, this intersubunit bridge protein is in fact critical.8/9

We observed a 40% reduction in overall protein synthesis in Gm10076 mutant keratinocytes. Ribosome profiling and RNA-seq revealed broad changes in the translational landscape, indicating that Gm10076 may contribute significantly to total cellular RPL41 levels. 7/9

We identified Gm10076 perturbation as the top depleted hit. This 25-amino-acid microprotein, encoded on the Gm10076 lncRNA, fully matches the RPL41 protein sequence, suggesting the existence of a second Rpl41 gene and prompting us to explore its role as intersubunit bridge. 6/9

We then validated 29 microproteins in a secondary screen both in vivo and in vitro, resulting in a high-confidence list of candidate microproteins that consistently displayed the same phenotype. 5/9

Notably, a cohort of 14 microprotein perturbations induced substantial transcriptional changes across the major epidermal cell types, suggesting that this subset of microproteins globally shapes gene expression and cellular function. 4/9

By combining scRNA-seq with sgRNA capture, we investigated 229 of these microproteins and systematically mapped cell-type-specific microprotein function at single-cell resolution. We discovered global and cell-type-specific gene expression alterations. 3/9

Spearheaded by the very talented @fabivf90 and another great collaboration with the Ellis lab, we used ribosome profiling to map microproteins in healthy epidermis and cancer, annotating more than 3000 novel ORFs. 2/9

Our genome encodes > 7000 microproteins that have been previously ignored in genome annotations. How do these microproteins impact tissue function? Here, we use an in vivo single-cell CRISPR screen to systematically explore microprotein function. 1/9.