Issues

Yan Zhao previews work from Qiming Sun and colleagues, which shows how Rab GTPases serve as cues for cargo receptor recruitment, mediating mitophagy, lipophagy, and xenophagy.

Yu Sun and Terytty Yang Li preview work from Li and colleagues, which describes a role for TMBIM-2 in the regulation of Ca²⁺ oscillations and coordinating the neuronal-to-intestinal mitochondrial UPR.

Sandkuhler and Mackenzie discuss the potential impact of protein-level discovery for individuals with TANGO2 deficiency disorder, a rare neurometabolic condition.

Shibuya reviews meiotic chromosome movements, highlighting telomere and nuclear membrane modifications crucial for accurate sexual reproduction.

Vostal et al. report two structures of complexes formed by valosin-containing protein (VCP), an unfoldase, and VCPIP1, a deubiquitinase. These data, along with biochemical analyses, suggest a model in which VCPIP1 is poised to cleave ubiquitin from protein substrates that translocate through VCP’s central pore.

FAcilitates Chromatin Transcription (FACT), which stabilizes chromatin during transcription and replication, is mysteriously enriched at mitotic kinetochores. In this paper, direct interactions between FACT and the 16-subunit constitutive centromere–associated network core of the chromatin-proximal kinetochore are reconstituted and reciprocal requirements for their stability are identified.

This paper shows that protein fragments derived from the CIZ1 gene disperse nuclear CIZ1-RNA assemblies, exposing underly loci and changing gene expression. The interference mechanism is implicated as a driver of epigenetic instability in early-stage breast cancers.

Zhang and co-authors show—through live-cell imaging of endogenously tagged proteins in C. elegans, RNAi-mediated protein depletion, and cell manipulations—that a population of Arp2/3 recruited via cell–cell contact makes an unexpected contribution to apical constriction.

This study reveals that adipocytes experiencing endoplasmic reticulum stress secrete ceramide in lipoprotein form to hepatocytes, activating the unfolded protein response by reducing membrane fluidity. The intercellular communication suggests the universality and importance of ceramide signaling in various cell types.

Stim1/2 deficiency desensitizes IP₃Rs without reducing membrane contact sites, abrogating Ca²⁺ signals driving the spreading of mouse neutrophils.

Mutations in the TANGO2 gene cause severe cardiomyopathies and rhabdomyolysis, particularly under stress. This study demonstrates that TANGO2 is an acyl-coenzyme A (CoA) binding protein located in the mitochondrial lumen. The researchers show that defects in TANGO2 disrupt the interaction with acyl-CoA, impairing lipid metabolism and mitochondrial function, leading to these pathologies.

Cells secrete proteins that cannot enter the ER–Golgi pathway of secretion. Our findings reveal that Golgi membranes are recycled to create new compartments called compartments for unconventional protein secretion and modified trans-Golgi network. These modified stations lack Golgi-specific glycosyltransferases and function to collect and sort cargo for secretion.

This study reveals the mechanism for yeast SAPK Hog1 activation by acetic acid stress. Stress granules induced by acetic acid exposure function as a scaffold to bring Hog1 together with its activating kinase Pbs2 without stimulation of the canonical HOG pathway beyond basal levels.

Li et al. reveal that neuronal mitochondrial stress induces subtle, continuous Ca²⁺ oscillations in a TMBIM-2-dependent manner, enhancing neurotransmission and influencing intertissue mitochondrial stress communication. Restoring Ca²⁺ balance provides a strategy to improve neuronal function and metabolic regulation during aging.

Trachsel-Moncho et al. identify the endosomal protein SNX10 as a modulator of piecemeal mitophagy of OXPHOS machinery components and mitochondrial homeostasis. They show that loss of SNX10 enhances mitochondrial protein degradation, reduces respiration, and increases ROS levels, leading to elevated cell death in vivo.

This study uncovers Rab GTPases as evolutionarily conserved signals mediating selective autophagy, targeting damaged mitochondria, lipid droplets, and pathogens for degradation. The research reveals a conserved mechanism across species, demonstrating how Rab GTPases regulate mitophagy, lipophagy, and xenophagy, with implications for maintaining cellular homeostasis.

Lysosomal acidification is crucial for cellular homeostasis, with impairment linked to aging and neurodegenerative diseases. We identify USP45 as a negative regulator of autophagy and lysosomal function, inhibiting V-ATPase localization to autolysosomes. USP45 regulates V-ATPase translocation via Coronin 1B–mediated actin modulation, suggesting therapeutic potential.

TDP-43 exhibits rhythmic expression, and its rhythmicity persists despite BMAL1 depletion in vivo, may modulate phospho-AMPKα(Thr172)/PFKP to alter glucose uptake/ATP production, and regulate USP13 mRNA splicing to affect BMAL1 ubiquitination. Its dysfunction disrupts murine circadian rhythms and cognition, linking TDP-43 to circadian-metabolic coupling in neurodegeneration.

Muneshige and Hatakeyama investigate the biogenesis of TORC1-containing signaling endosomes in yeast. They find that the membrane is supplied by vacuoles during the formation of signaling endosomes in a process mediated by the membrane-cutting CROP complex and promoted by TORC1 kinase activity.

Specific circumstances where membrane contact is needed for vesicular transport remain to be defined. The current study finds that a critical lipid is delivered through membrane contact to support the fission stage of a model intracellular transport pathway.

Doan and Monk employ a combination of zebrafish and mouse models in development, adulthood, and injury to demonstrate that the guanine nucleotide exchange factor Dock1 functions with Rac1 in Schwann cells to regulate radial sorting and proper repair.

Membrane contact sites (MCS) mediate signaling responses to extracellular stimuli, yet mechanisms that regulate their density are poorly understood. Nath et al. find that in Drosophila photoreceptors, Ca²⁺ influx through plasma membrane channels regulates MCS density through extended synaptotagmin, highlighting the role of Ca²⁺ signaling in regulating MCS density to meet ongoing physiological needs.