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Using primary astrocytes and neural precursors, which naturally express both CDC42 isoforms, the authors show that the short carboxy-terminal sequence, which distinguishes the two isoforms, dictates different cell functions by influencing the protein intracellular localization.

McGory et. al uncover a linkage between the disordered kinetochore protein Spc105 and the dynein-targeting RZZ complex. Compromising the connection increases the prevalence of erroneous kinetochore–microtubule attachments. The authors conclude that Spc105 multimerization helps recruit a pool of RZZ that promotes accurate chromosome segregation.

Article

Using live-cell single-molecule imaging, Tirumala and Redpath et al. show that the motor protein cytoplasmic dynein is activated in a stochastic manner when it encounters preformed dynactin–cargo complexes on microtubules. The resulting cargo movement in short bursts cumulatively results in long-range transport into late endosomal compartments.

Yoshii and Barral discover that lateral diffusion barriers compartmentalize the membranes of yeast mitochondria into mother, bud, and tethered domains in a regulated manner, independent of the fission machinery.

The role of mechanical forces in blood flow is pivotal in vascular health and the development of diseases like atherosclerosis. This study employs multiomics approaches to elucidate how various flow patterns influence gene regulation in endothelial cells, pinpointing critical super-enhancers involved in mechanotransduction.

The V-ATPase–ATG16L1 axis mediates conjugation of LC3 on perturbed lysosomal membranes independently of autophagy. Eguchi, Sakurai et al. reveal that this axis facilitates recruitment of LRRK2 to stressed lysosomes, thereby promoting release of lysosomal contents and maintaining their morphology.

Inoue et al. demonstrate that the microtubule- and actin-binding protein MAP1B promotes invadopodia stabilization, invasion, and tumorigenesis in triple-negative breast cancer cells by preventing autophagic degradation of the pro-invasive protein Tks5 and propose the MAP1B–Tks5–cortactin axis as a potential therapeutic target for TNBC.

Deng et al. demonstrated that TNF/IFNγ-induced cancer cell death occurs through the direct binding of IRF1 to the CYLD and CASP8 promoters, enhancing their expression. Additionally, they found that ELAVL1 binds to CASP8 mRNA, stabilizing it and contributing to TNF-initiated death.

Baker et al. demonstrate dysregulation of the intermembrane space disaggregase CLPB leads to aggregation of local quality control proteins, including SPY complex members (STOML2, PARL, and YME1L1). This drives aberrant downstream substrate turnover and perturbs proteostatic control. These QC perturbations may underscore CLPB disease pathology.

USP8 depletion causes aberrant accumulation of K63-linked ubiquitin chains on endosomes, where TAB2/3 and p62 are recruited, and activates NF-κB and Nrf2. The results demonstrate that USP8 is a gatekeeper of misdirected ubiquitin signals to prevent immune and stress responses.

Wu et al. unveil a GTPase-dependent regulatory mechanism for autophagosomal components recycling (ACR). Rab32 and Rab38, located on autolysosomes, regulate recycler complex formation and the interaction between recycler-cargo and the dynactin complex. This study reveals an unexplored regulatory mechanism for ACR involving Rab32 family proteins.

The sperm annulus, a septin-based ring structure, migrates distally along the flagellum to form a midpiece/principal piece boundary. Hoque et al. show that the membrane-binding Cby3/ciBAR1 complex is indispensable for the precise stoppage of the annulus at the midpiece/principle piece junction of the sperm tail.

Pan et al. describe that the stability of cyclin D1 mRNA fluctuates throughout the cell cycle, controlled by PC4, a small RNA binding protein modified by cell cycle–dependent phosphorylation and ubiquitination. This regulation impacts cell cycle progression and tumorigenesis, suggesting PC4 as a promising therapeutic target for hepatocellular carcinoma treatment.

HEATR5 proteins have conserved roles in traffic mediated by the clathrin adaptor AP1. Marmorale et al. found that yeast HEATR5 operates in two distinct complexes, with only one binding to AP1. These complexes are distinguished by cofactors that compete for a conserved interface on HEART5.

Review

Hämälistö et al. review how B lymphocytes have adopted specialized ways to use endolysosomal vesicles to promote adaptive immune responses.

Kim et al. review how mitochondria-to-nuclear communication promotes proteostasis and immunity.

Tools

Two small molecules, G3Ia and G3Ib, block a protein interaction surface of G3BP1, leading to stress granule inhibition and/or dissolution. These new tools will aid in understanding the biology of stress granules and hold promise for therapeutic targeting of stress granules.

Spotlight

TNF signaling does not result in cell death unless multiple inhibitory signals are overcome, which can be accomplished by simultaneous signaling through IFNγ. In this issue, Deng and colleagues dissect the mechanisms by which IFNγ signaling combines with TNF to mediate cell death through caspase-8, discussed by James E. Vince.

Chen and Liu preview work from the Takemaru lab that describes how a Cby3/ciBAR1 complex controls positioning of the annulus in the sperm flagellum.

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