Biology subjects

Deuerling, E.

Publications and source records attributed to Deuerling, E..

3 recordsLinked to original sources

bioRxiv2026

Nucleolus transformation and Pol1 activity pattern dual transcriptomes of neuronal subtype identity

Gene expression directs neuronal fate during development with multiple RNA polymerases in the nucleus. mRNA transcribed by Pol2 ultimately depends on the rRNA transcribed by Pol1 in the nucleolus, which generates a ribosome pool to control mRNA translation. How Pol1 activity is synchronized with the Pol2 transcriptome to direct gene expression and neuronal fate is unknown. By creating a high-resolution map of nucleoli in the developing neocortex, we discover that the nucleolus is restructured in neuronal lineages with distinct Pol1 activity. With a new method for rRNA and mRNA dual-transcriptome sequencing in single-cells, we reveal that rRNA transcription is neuronal subtype and stage specific. Rather than a general feature of neural progenitor differentiation, rRNA production peaks transiently in post-mitotic subcortical projection neurons, which have atypical nucleoli containing a single, large cavity. Pol1 inactivation redirects these neurons towards a distinct fate that expresses a hybrid of subcortical and intracortical projection neuron markers. Thus, nucleolar architecture and Pol1 activity pattern dual rRNA-mRNA transcriptome signatures of neuronal subtype identity.

neuroscience↗

bioRxiv2025

NAC controls nascent chain fate through tunnel sensing and chaperone action

The nascent polypeptide-associated complex (NAC) is a conserved ribosome-bound factor with essential yet incompletely understood roles in protein biogenesis. Here, we show that NAC is a multifaceted regulator that coordinates translation elongation, cotranslational folding, and organelle targeting through distinct interactions with nascent polypeptides both inside and outside the ribosome exit tunnel. Using NAC-selective ribosome profiling in C. elegans, we identify thousands of sequence-specific NAC binding events across the nascent proteome, revealing broad cotranslational engagement with hydrophobic and helical motifs in cytosolic, nuclear, ER, and mitochondrial proteins. Unexpectedly, we discover an intra-tunnel sensing mode, where NAC engages ribosomes with extremely short nascent polypeptides inside the exit tunnel in a sequence-specific manner. These early NAC interactions induce an early elongation slowdown that tunes ribosome flux and prevent ribosome collisions, linking NACs chaperone activity to kinetic control of translation. We propose that NAC action protects aggregation-prone intermediates by shielding amphipathic helices thus promoting cytonuclear folding and supporting mitochondrial membrane protein biogenesis and ER targeting by early recognition of signal sequences and transmembrane domain. Our findings establish NAC as an early-acting, multifaceted orchestrator of cotranslational proteostasis, with distinct mechanisms of action on nascent chains depending on their sequence features and subcellular destinations.

biochemistry↗

bioRxiv2022

Molecular basis of the TRAP complex function in ER protein biogenesis

The Translocon Associated Protein (TRAP) complex resides in the endoplasmic reticulum (ER) membrane and interacts with the Sec translocon and the translating ribosome to facilitate biogenesis of secretory and membrane proteins1-4. TRAP is essential for the secretion of many hormones, and its key role in the production of the hormone peptide insulin has been particularly well established5,6. The mechanism by which TRAP engages ribosomes and the translocon to facilitate translocation of protein clients in the secretory pathway is not clear. Here, we reveal the molecular architecture of the mammalian TRAP complex and how it engages the translating ribosome associated with Sec61 translocon on the ER membrane. The TRAP complex is anchored to the ribosome via a long tether and its position relative to the ribosome and the translocon is further stabilized by a finger-like loop. This spatial arrangement positions a cradle-like lumenal domain of TRAP below the protein conducting pore of the translocon for interactions with translocated nascent chains. The biological importance of these key interactions is evident by structure-guided TRAP mutations in C. elegans that lead to growth deficits associated with increased ER stress and defects in insulin secretion. Our findings elucidate the molecular basis of the TRAP complex in the biogenesis and translocation of proteins at the ER.

molecular biology↗