People & Ideas
Feng and colleagues discuss work from the labs of Spencer Freeman and Sergio Grinstein as well as the lab of Xiaochen Wang demonstrating the lysosomal H+/Cl− exchanger ClC-7 drives luminal Cl− accumulation to activate acidic hydrolases.
David Sacks and colleagues review the crosstalk between cell surface receptors and the IQGAP scaffold proteins.
Sell et al. use mass cytometry to analyze the impact of colorectal cancer driver mutations in organoids. They find that nodes of the cell signaling network remain coupled to cell differentiation states during cancer progression and provide links between phospho-protein activities and transcriptome modules.
A PI3K-calcium-Nox axis primes leukocyte Nrf2 to boost immune resilience and limit collateral damage
Macrophages activate the cytoprotective factor Nrf2 upon phagocytic ROS production via PI3K-calcium-Nox signaling during immune surveillance. This protective response is crucial to sustain vital immune functions and limit macrophage acquisition of senescence-like features. Macrophage Nrf2 also acts non-autonomously to limit bystander damage to adjacent healthy tissues.
Flores Servin, Brown, and Straight find that vertebrate CENP-A assembly is restricted to G1 phase by two inhibitory activities, phosphorylation of HJURP and competitive binding of M18BP1.S to CENP-C, that prevent HJURP’s metaphase centromere localization. Removal of these inhibitory activities causes CENP-A assembly in metaphase.
Amm et al. define an amphipathic helix in Ndc1, an essential nuclear pore and spindle pole body transmembrane protein, genetically interacting with similar motifs in Nup53 and Nup59. This work suggests that the nuclear pore formation depends on a balance between amphipathic motifs in different nucleoporins.
Homophilic interaction of cell adhesion molecule 3 coordinates retina neuroepithelial cell proliferation
The study reveals the homophilic interaction of cell adhesion molecule 3 as an intercellular mechanism underlying the overproliferation of “winner” cells in p15-driven cell competition of retinal progenitor cells.
Zhang et al. identify the lysosomal Cl−/H+ antiporter CLH-6/ClC-7 as an important factor for protecting lysosome integrity. They reveal that CLH-6 maintains the luminal chloride levels required for cathepsin activity, thus facilitating substrate digestion to preserve lysosomal membrane stability.
ClC-7 drives intraphagosomal chloride accumulation to support hydrolase activity and phagosome resolution
Wu et al. demonstrate that ClC-7, a lysosomal chloride-proton exchanger, drives the accumulation of chloride ions into mature phagosomes. In turn, high luminal chloride supports the activity of glycosidases, nucleases, and proteases and enables their breakdown of ingested targets.
Saygili Demir, Sabine et al. identify proliferating valve sinus endothelial cells as a main source for repair of postnatal lymphatic vessels. The process is driven by mechanosensitive mTORC1 activation, which controls both proliferation and protein synthesis. These findings provide a mechanistic explanation for increased incidence of lymphedema in rapamycin-treated patients.
PIM1 kinase promotes prostate cancer invasion by directly phosphorylating ABI2, which increases WAVE regulatory complex activity and enhances actin dynamics to drive tumor cell protrusion. These findings represent the first signal transduction pathway linking hypoxia to the regulation of actin cytoskeletal dynamics and reveal PIM1 as a new target to opposing hypoxia-induced metastasis.
RNA recruitment switches the fate of protein condensates from autophagic degradation to accumulation
Protein condensates can evade autophagic degradation under stress or pathological conditions. Zheng et al. show that partitioning of mRNAs modulates protein phase separation and transition, enabling protein condensates to escape from autophagic degradation to confer stress adaptation in C. elegans.
Shelke et al. show that disruption of the BORC–ARL8–HOPS pathway increases exosome secretion by impairing fusion of multivesicular endosomes with lysosomes, and thus increasing the availability of intraluminal vesicles for release into the extracellular space.
Ralhan et al. show that neurons release peroxidated lipids and iron as lipid-rich particles by autolysosomal exocytosis during oxidative stress. This protects neurons from cell death by ferroptosis.
Li et al. delineate a signaling pathway responsible for the polarized assembly of cortical F-actin in rapidly migrating cells. Their results reveal that, apart from its well-defined role in the formation of the protrusions at the cell front, the Arp2/3 complex-based actin carries out a previously unappreciated function in building the rear cortical subcompartment.
O’Shaughnessy et al. identify a putative ubiquitin E3 ligase that is required for cytoskeleton turnover during Toxoplasma division. Remarkably, knockout of the E3 ligase suppresses the loss-of-function of Toxoplasma ERK7, unveiling an essential pathway that regulates protein homeostasis during division of this ubiquitous parasite.
Udi et al. present a new method for quantitative subcellular fractionation of a wide range of mammalian cells while maintaining nuclear integrity. This method provides a fast and reliable means to perform mass spectrometry and DeDuvian enrichment analyses for the different cellular compartments.
A survey of intracellular localization of 200 mRNAs and encoded proteins in the Drosophila larval nervous system. Post-transcriptional regulation is the norm and ∼10% of transcripts localize at tips of glia/neurons, with potentially important functions. A novel browsable resource of ∼1,300 figures is provided.