Molecular Cell最新文献

The circadian clock drives daily rhythms of gene expression and physiology. Advances in next-generation DNA sequencing have provided extensive insights into RNA expression, but more functional information at the protein level with sufficient depth has been limited by technical challenges. In this study, we generated a comprehensive mouse circadian proteome atlas (https://chronoproteinology.org/circadian_atlas) by analyzing 32 tissues, including the suprachiasmatic nucleus (SCN), using the next-generation mass spectrometer Orbitrap Astral. Data-independent acquisition of 584 samples, including developmental samples, revealed the spatiotemporal profiles of about 19,000 proteins. Proteome and phospho-proteome analyses of whole-cell and nuclear proteins in the liver revealed circadian changes in protein quantity and quality, as well as global changes in hPER2-S662G mutant mice, a genetic model of human familial advanced sleep phase (FASP). This multi-tissue circadian proteome atlas provides a fundamental resource for understanding when, where, and which proteins are expressed and function.

Approximately 10% of eukaryotic proteins are folded by the TRiC/CCT complex (TCP1-ring complex, also called CCT for cytosolic chaperonin containing TCP1), and only open-state TRiC can bind with programmed cell death 5 (PDCD5). However, the physiological role of the PDCD5-TRiC interaction remains elusive. Here, we show that PDCD5 is required for flagellum biogenesis and ciliogenesis and present the PDCD5-TRiC structures in their open states at near-atomic resolution. Mechanically, we find that PDCD5 promotes substrates release by competing with PhLP2A to interact with TRiC, and the depletion of PDCD5 traps flagellum- and cilium-associated proteins within TRiC, finally leading to malformed flagella of spermatids and cilia in mouse ciliated cells. Moreover, we demonstrate that the function of PDCD5 in flagellum biogenesis and ciliogenesis depends on the interaction with TRiC by its C terminus. These findings identify PDCD5 as a TRiC regulator to promote a subset of proteins release.

In this issue of Molecular Cell, Kral et al.¹ identify a targetable, novel mechanism of pancreatic ductal adenocarcinoma (PDAC) tumorigenesis via SRSF1 splicing-mediated regulation of an Alu-derived exon in Aurora kinase A (AURKA).

The ribosome-associated quality control (RQC) pathway resolves stalled ribosomes. As part of RQC, stalled nascent polypeptide chains (NCs) are appended with CArboxy-Terminal amino acid tails (CAT tails) in an mRNA-free, non-canonical elongation process. The relationship between CAT tail composition (alanine [Ala] and threonine [Thr] in yeast) and function has remained unknown. Using biochemical approaches in yeast, we discovered that mechanical forces on the NC regulate CAT tailing. We propose that CAT tailing initially operates in "extrusion mode," which increases NC lysine accessibility for on-ribosome ubiquitylation. Thr in CAT tails prevents the formation of polyalanine, which forms α-helices that lower extrusion efficiency and disrupt termination of CAT tailing. After NC ubiquitylation, pulling forces on the NC switch CAT tailing to an Ala-only "release mode," which facilitates NC release and degradation. Failure to switch from extrusion to release mode leads to the accumulation of NCs on large ribosomal subunits and proteotoxic aggregation of Thr-rich CAT tails.