Mutations that increase LRRK2 kinase activity have been linked to Parkinson’s disease and Crohn’s disease. LRRK2 is also activated by lysosome damage. However, the endogenous cellular mechanisms that control LRRK2 kinase activity are not well understood. In this study, we identify signaling through stimulator of interferon genes (STING) as an activator of LRRK2 via the conjugation of ATG8 to single membranes (CASM) pathway. We furthermore establish that multiple chemical stimuli that perturb lysosomal homeostasis also converge on CASM to activate LRRK2. Although CASM results in the lipidation ..read more

Tubulin polyglutamylation is essential for maintaining cilium stability and function, and defective tubulin polyglutamylation is associated with ciliopathies. However, the regulatory mechanism underlying proper axonemal polyglutamylation remains unclear. He et al. (https://doi.org/10.1083/jcb.202405170) discovered that Cdk7/Cdk6/FIP5 phosphorylation cascade controls the ciliary import of tubulin glutamylases, thereby modulating axoneme polyglutamylation and ciliary signaling ..read more

The accumulation of defective polypeptides in cells is a major cause of various diseases. However, probing defective proteins is difficult because no currently available method can retrieve unstable defective translational products in a soluble state. To overcome this issue, there is a need for a molecular device specific to structurally defective polypeptides. In this study, we developed an artificial protein architecture comprising tandemly aligned BAG6 Domain I, a minimum substrate recognition platform responsible for protein quality control. This tandem-aligned entity shows enhanced affini ..read more

Cajal bodies are essential sites for the biogenesis of small nuclear and nucleolar ribonucleoproteins. In this issue, Courvan and Parker discuss new work from Neugebauer and colleagues (https://doi.org/10.1083/jcb.202305081) that carefully profiles Cajal Body components and finds an unexpected role for 60S ribosomal proteins ..read more

How cells establish the interphase genome organization after mitosis is incompletely understood. Using quantitative and super-resolution microscopy, we show that the transition from a Condensin to a Cohesin-based genome organization occurs dynamically over 2 h. While a significant fraction of Condensins remains chromatin-bound until early G1, Cohesin-STAG1 and its boundary factor CTCF are rapidly imported into daughter nuclei in telophase, immediately bind chromosomes as individual complexes, and are sufficient to build the first interphase TAD structures. By contrast, the more abundant Cohesi ..read more

Epithelial cells can become polyploid upon tissue injury, but mechanosensitive cues that trigger this state are poorly understood. Using an Madin Darby Canine Kidney (MDCK) cell knock-out/reconstitution system, we show that α-catenin mutants that alter force-sensitive binding to F-actin or middle (M)-domain promote cytokinesis failure and binucleation, particularly near epithelial wound-fronts. We identified Leucine Zipper Tumor Suppressor 2 (LZTS2), a factor previously implicated in abscission, as a conformation sensitive proximity partner of α-catenin. We show that LZTS2 enriches not only at ..read more

The interplay between ribosomal protein (RP) composition and mitochondrial function is essential for energy homeostasis. Balanced RP production optimizes protein synthesis while minimizing energy costs, but its impact on mitochondrial functionality remains unclear. Here, we investigated haploinsufficiency for RP genes (rps-10, rpl-5, rpl-33, and rps-23) in Caenorhabditis elegans and corresponding reductions in human lymphoblast cells. Significant mitochondrial morphological differences, upregulation of glutathione transferases, and SKN-1–dependent oxidative stress resistance were observed acro ..read more

Upon invasion into the host cell, a subset of bacterial pathogens resides exclusively in the cytosol. While previous research revealed how they reshape the plasma membrane during invasion, subvert the immune response, and hijack cytoskeletal dynamics to promote their motility, it was unclear if these pathogens also interacted with the organelles in this crowded intracellular space. Here, we examined if the obligate intracellular pathogen Rickettsia parkeri interacts with the endoplasmic reticulum (ER), a large and dynamic organelle spread throughout the cell. Using live-cell microscopy and tra ..read more

Many cancer cells exhibit increased amounts of paucimannose glycans, which are truncated N-glycan structures rarely found in mammals. Paucimannosidic proteins are proposedly generated within lysosomes and exposed on the cell surface through a yet uncertain mechanism. In this study, we revealed that paucimannosidic proteins are produced by lysosomal glycosidases and secreted via lysosomal exocytosis. Interestingly, lysosomal exocytosis preferentially occurred in the vicinity of focal adhesions, protein complexes connecting the actin cytoskeleton to the extracellular matrix. Through genome-wide ..read more

While membrane proteins such as ion channels continuously turn over and require replacement, the mechanisms of specificity of efficient channel delivery to appropriate membrane subdomains remain poorly understood. GJA1-20k is a truncated Connexin43 (Cx43) isoform arising from translation initiating at an internal start codon within the same parent GJA1 mRNA and is requisite for full-length Cx43 trafficking to cell borders. GJA1-20k does not have a full transmembrane domain, and it is not known how GJA1-20k enables forward delivery of Cx43 hemichannels. Here, we report that a RPEL-like domain a ..read more