ON THE COVER
Image shows an “APPL tree.” Dual-color TIRF immunofluorescence images of APPL1 (green) and APPL2 (red) endosomes in H1975 cells after 20 ng/ml EGF stimulation. Image © Lakoduk et al., 2019. See page 1928.
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Ktistakis discusses work from Melia and colleagues that implicates ER localized ATG2 in the supply of lipids to forming autophagosomes.
Van Den Bosch highlights the discovery by Kalinski et al. of Miro1 as an HDAC6 substrate that regulates mitochondrial trafficking in neurons and axon regeneration.
Toivanen and Furic preview work from the Trotman laboratory showing the phosphatase PHLPP2 controls Myc stability, suggesting a new way to target Myc in prostate cancer.
Zhang and Balachandran preview new findings from Sai et al. revealing that necroptosis signaling mediators can directly inhibit Listeria replication in gut epithelium.
Valverde et al. show that the autophagy protein ATG2 functions in autophagosome biogenesis by transferring lipids at ER–autophagosome contact sites.
This work reveals that Rap1 GTPases bind directly to the talin1 F1 domain and by cooperating with a unique lipid-dependent amphipathic helix in the F1 domain effect talin1-mediated integrin activation.
How macroH2A, a histone variant involved in silencing gene expression, is inherited from parent to daughter cells is unclear. Using a combination of imaging, biochemical, and genomic approaches, Sato et al. describe how newly synthesized macroH2A is incorporated predominantly in the G1 phase of human mitosis, targeting heterochromatic regions.
Nakajima et al. reveal a novel mechanism of planar spindle alignment through junctional tumor suppressors Scrib/Dlg and 14-3-3 proteins in the Drosophila wing disc epithelium. Their results suggest that 14-3-3 proteins interact with Scrib/Dlg to control planar spindle orientation and maintain epithelial architecture.
Aksu et al. present structures of the biportin Pdr6/Kap122 bound to its nuclear import cargo Ubc9 and to RanGTP and its export cargo eIF5A, illuminating an almost complete transport cycle and providing unexpected insights into the evolution of nuclear transport receptors.
Respiratory chain inactivation links cartilage-mediated growth retardation to mitochondrial diseases
Children with mitochondrial diseases often present with slow growth and short stature, but the underlying mechanism remains unclear. In this study, Holzer et al. provide in vivo evidence that mitochondrial respiratory chain dysfunction induces cartilage degeneration coincident with altered metabolism, impaired extracellular matrix formation, and cell death at the cartilage–bone junction.
Extracellular stimuli in the injured CNS, such as chondroitin sulfate proteoglycans, inhibit axon growth through activation of the small GTPase RhoA. This RhoA activation increases intracellular Ca2+ that converges on an HDAC6-dependent pathway to deacetylate Miro1. Deacetylation of Miro1 decreases mitochondrial transport and attenuates axon growth.
How mitochondria damaged in distal axons are cleared is not understood. Zheng et al. find that axonal mitochondria return to neuronal soma for mitophagy after ischemic insult. These spatial features of neuronal mitophagy provide insight into how neurons control mitochondrial quality under pathological conditions.
Zhou et al. identify the mechanism of autophagosome (AP) closure. They show that Rab5 GTPase regulates an interaction between the ESCRT subunit Snf7 and Atg17 to bring ESCRT to APs where it catalyzes AP closure. These findings highlight the convergence of the endocytic and autophagic pathways at this step.
Mutant p53 amplifies a dynamin-1/APPL1 endosome feedback loop that regulates recycling and migration
Feedback loops arising from crosstalk between early endocytic trafficking and receptor signaling can be co-opted or amplified in cancer cells to enhance their metastatic abilities. Lakoduk et al. reveal that mutant p53 upregulates dynamin-1 expression and recruitment of the APPL1 signaling scaffold to a spatially localized subpopulation of endosomes to increase receptor recycling and cell migration.
Nowak et al. show that loss of the AKT-inactivating phosphatase PHLPP2 paradoxically blocks prostate tumor growth and metastasis. PHLPP2, they find, is critical for MYC stability, suggesting that PHLPP2 inhibitors may present a therapeutic opportunity to target MYC.
Campbell et al. show that force stimulates PAK2 activation at cell–cell junctions, where it protects cells under force from death and plays a key role in linking force-induced mechanotransduction, metabolism, and cell survival.
Tunneling nanotubes (TNT) are membranous tubes that connect two cells, but their functional roles and mechanism of biogenesis remain obscure. Sharma and Subramaniam demonstrate that Rhes, a brain-enriched protein, increases biogenesis of TNT-like cellular protrusions or “Rhes tunnels” through which Rhes travels from cell to cell and transports Huntington disease (HD) protein.
Necroptosis mediators RIPK3 and MLKL suppress intracellular Listeria replication independently of host cell killing
The RIPK3-MLKL pathway protects epithelial cells from Listeria monocytogenes invasion. Sai et al. find that Listeria infection activates MLKL but does not induce its oligomerization or necroptotic cell death. Instead, Listeria-activated MLKL directly targets intracellular bacteria and suppresses their replication.
The authors describe a system for engineering proteases. They evolved SUMOEu/protease pairs that are compatible with eukaryotic protein expression and used SUMOEu-assisted affinity chromatography to identify Ubc9 as a nuclear import cargo and eIF5A as well as eEF2 as export substrates of Pdr6.
Peroxisomes import proteins with a C-terminal SKL sequence by a poorly understood mechanism. Romano et al. use Xenopus egg extracts to study peroxisome import in vitro. The novel assay recapitulates import in vivo and provides mechanistic insights.
Rab small GTPases (∼60 genes in mammals) are the master regulators of intracellular membrane trafficking. Homma et al. establish a comprehensive collection of knockout epithelial cell lines for all the mammalian Rabs, revealing that Rab6 is required for basement membrane formation and soluble cargo secretion.
The central apparatus is an essential component of “9+2” cilia. Zhao et al. identify more than 40 new potential components of the central apparatus of Chlamydomonas. Many are conserved and will facilitate genetic screening of patients with a form of primary ciliary dyskinesia that is difficult to diagnose.