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Issues

In Memoriam

Thoru Pederson discusses the life and achievements of Sheldon Penman, who passed away on September 27, 2021.

Spotlights

McPhedran and Lum discuss exciting new results from Harris et al. reporting that Fbxo7 links ubiquitination to T cell metabolism through phosphofructokinase.

Akmeriç and Gerhardt highlight work from Coon et al., which shows that sustained laminar shear stress regulates Klf2 expression in endothelial cells via mitochondrial remodelling and mitophagy.

Fonseca and Chakrabarti preview work from Wang et al. describing that the SARS-CoV-2 protein ORF10 enhances the degradation of ciliary proteins, thereby resulting in the loss of cilia in respiratory epithelial cells.

Jeanne Stachowiak highlights work from Cail and colleagues, which demonstrates that clathrin’s primary function is stabilizing membrane curvature during vesicle formation rather than scaffold recruitment.

Perspectives

Deretic and Lazarou conceptualize atg8ylation as a membrane stress and remodeling response, with autophagy and nonautophagic processes as its outputs.

Reports

The machinery and cellular mechanisms involved in multivesicular body (MVB) biogenesis are not fully understood. Shi et al. reveal that the F-actin crosslinker FLN-2/filamin acts as a bridging molecule that docks MVB on the actin cytoskeleton to facilitate MVB biogenesis.

Articles

The formation of high-order molecular assemblies is common among kinases and stress sensor proteins. However, no such mechanism has been described for the ISR kinase PKR. This study shows that PKR forms clusters in response to stress to fine-tune enzyme–substrate encounters and buffer PKR signaling.

Fbxo7 has dual roles, ubiquitining proteins and activating the kinase Cdk6. The authors show both Fbxo7 functions converge on phosphofructokinase (PFKP), a gatekeeper of glycolysis, inhibiting its function. Fbxo7 deficiency increases glycolysis and reduces T cell activation and viability, demonstrating its important role in regulating metabolism.

The authors identify the negative regulating function of STING in energy stress-induced autophagy in Drosophila, mice exercising model, and cultured cells. Mechanistically, STING downregulates the autophagic fusion process by sequestering autophagic SNARE protein STX17 on ER and inhibits its translocation toward complete autophagosome.

UPRmt increases mitochondrial quality control proteins and induces longevity. But how do the rescuing proteins enter mitochondria, as UPRmt is initiated with dampened mitochondrial import? The study by Xin et al. shows that enhanced mitochondrial import mediates UPRmt-induced lifespan extension upon UPRmt activation.

Coon et al. identify an anti-inflammatory signaling pathway mediated by laminar shear stress stimulation of endothelial cells, whereby mitochondrial signaling and the adaptor protein, p62, promote ERK5 activation and enhance KLF2 expression. This accounts for relatively high KLF2 expression in laminar shear stimulated conditions compared to disturbed shear stimulation.

Hancock-Cerutti et al. demonstrate that deletion of the autosomal recessive Parkinson’s disease (PD) gene VPS13C in a model cell line causes significant perturbations of lysosomal lipid composition and leads to activation of the cGAS-STING pathway, with potential implications for PD pathogenesis.

Wang et al. report that the SARS-CoV-2 ORF10 promotes IFT46 degradation via stimulating CUL2ZYG11B activity, thereby impairing both cilia biogenesis and maintenance. The study provides a pathological mechanism connecting COVID-19 symptoms with cilia dysfunction.

Zhang et al. reconstitute branching microtubule nucleation using native and recombinant human augmin–γ-TuRC complex and highlight the importance of the adaptor protein NEDD1 and CDK1/PLK1-mediated phosphorylation in this process. This study also unravels a novel augmin’s oligomerization-dependent mechanism for γ-TuRC activation.

Unconventional protein secretion (UPS) mediates protein exocytosis without entering the ER-Golgi secretory route. Here, Wang et al. report SMGL-1 acts as a guanine nucleotide exchange factor for RAB-8 to facilitate apical UPS of integral proteins in Caenorhabditiselegans intestinal epithelia.

Cail et al. demonstrate that induced nanoscale membrane curvature can recruit endocytic proteins and produce cargo-laden vesicles without the coat protein clathrin; however, the induced curvature does not bypass AP2 and FCHo1/2 functions. This work suggests that the essential function of clathrin is to physically stabilize the curvature of the evolving vesicle.

Most forms of cancer involve a step where cells move out of an epithelial layer, a step that requires the loss of the apical domain of epithelial cells. We show how this loss of polarity is regulated at multiple levels by key polarity proteins.

Drosophila border cells are an established in vivo model for collective cell migration. Miao et al. show that a spliceosome C complex component, Cactin, is essential to coordinate apicobasal polarity among collectively migrating cells and that migrating cells are more sensitive to perturbed polarity than stationary epithelial cells.

Huang and Winklbauer show that diffuse cytoplasmic Prickle1 and Dishevelled-2 regulate cortical F-actin assembly and cortical tension to promote cell–cell adhesion and cell rearrangement in the Xenopus gastrula, whereas cell separation and trailing edge retraction are correlated with Pk-1 puncta.

Abu Rmaileh et al. demonstrate that the axon guidance adaptor protein DPYSL2 is essential for promoting breast cancer cell migration. Specifically, this adaptor protein interacts with JAK1 to regulate STAT3 signaling and subsequently vimentin expression.

Ahmad and colleagues report that presynaptic accumulation of NRG3 involves multiple processes that include release of the EGF-containing domain from the TGN following BACE1 cleavage, transcytosis from somatodendritic to axonal plasma membranes, and selective retention at glutamatergic terminals through trans-synaptic interactions with postsynaptic ErbB4 receptors.

Tools

Vega-Lugo, da Rocha-Azevedo et al. analyze three-color microscopy images to determine whether the colocalization between two molecular entities is influenced by their colocalization with a third entity, providing evidence for cooperativity or competition between molecular interactions and for their enhancement or suppression at subcellular locations.

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