In this issue, Bowman et al. describe an unprecedented mechanism where two sorting complexes, AP-3 and BLOC-1, the latter bound to syntaxin 13, work as a fail-safe to recognize sorting signals in VAMP7, a membrane protein required for fusion to melanosomes. Their observations define one of the first examples of distributed robustness in membrane traffic mechanisms.
Centromeric transcription is critical for proper centromere function, but its exact role remains elusive. By manipulating the activity of centromeric transcription, Chen et al. report that a major function of centromeric transcription in human cells is to maintain centromeric cohesion.
Nuclear pore complexes mediate nuclear transport and are highly modified with O-linked N-acetylglucosamine (O-GlcNAc) on FG repeat domains. Using a new quantitative live-cell imaging assay, Yoo and Mitchison demonstrate acceleration of nuclear import and export by O-GlcNAc modification.
Pal et al. discover that podosomes and invadopodia ubiquitously recruit membrane-bound DNase X, which readily degrades extracellular double-stranded DNA. The authors also show that macrophages, in response to immunogenic materials, form podosomes that degrade bacterial DNA on surfaces.
Kumbhar et al. identify a new poly(ADP-ribose) interaction domain within the demethylase KDM5A that acts in concert with the histone variant macroH2A1.2 to localize this enzyme to DNA lesions, where it regulates damage-associated transcriptional responses and promotes DNA double-strand break repair.
Iemura et al. find that chromosome oscillation during metaphase facilitates correction of erroneous kinetochore–microtubule attachments through Hec1 phosphorylation by Aurora A on the spindle. Chromosome oscillation is attenuated in cancer cell lines, which may be a cause of chromosomal instability.
Su et al. show that SUMOylation stabilizes bioriented kinetochore–microtubule attachments in mitosis to allow timely anaphase onset. They identify the shugoshin pericentromeric adaptor protein and the chromosome passenger complex as SUMOylation targets, which lead to dampening of error correction pathways.
Meitinger, Kong, Ohta, et al. show that loss of the ubiquitin ligase TRIM37 leads to the formation of ectopic condensates scaffolded by the centrosomal protein centrobin. Condensates nucleate microtubules in mitosis, elevating the frequency of multipolar spindle intermediates and mitotic errors, which they propose underlie the TRIM37 loss–associated human disease mulibrey nanism.
ER-mitochondria contacts respond to cellular stress. Chai et al. reveal that in response to hypoxia, USP19, an ER-resident deubiquitinase, accumulates at ER-mitochondria contact sites where USP19 deubiquitinates and stabilizes FUNDC1, thereby promoting Drp1 oligomerization and subsequent hypoxia-induced mitochondria division.
Sequential dynein effectors regulate axonal autophagosome motility in a maturation-dependent pathway
Neuronal autophagosomes form in the distal axon and mature via lysosomal fusion during transport to the soma. Dynein regulators JIP1, HAP1, and JIP3 function on autophagosomes depending on location and autophagosomal maturity. In this pathway, transport and maturity are tightly linked to maintain neuronal health.
Atlastin mediates fusion of ER membranes. Liu et al. show that Atlastin 2/3 also contribute to the recruitment and stabilization of ULK1 and ATG101 at the autophagosome formation sites on the ER.
The work identifies a noncanonical autophagic program mediated by the hominid-specific LC3C paralog functioning downstream from the von Hippel–Lindau tumor suppressor. The program targets for lysosomal degradation postdivision midbodies in a mechanism requiring FIP200/ATG13/ULK3 and UVRAG/RUBCN/PIK3C2A/BECN1 complexes as well as the C-terminal peptide of LC3C.
A BLOC-1–AP-3 super-complex sorts a cis-SNARE complex into endosome-derived tubular transport carriers
Bowman et al. show that in melanocytes, the vSNARE VAMP7 is sorted from endosomes into tubular membrane transport carriers bound for maturing melanosomes in a complex with the tSNARE syntaxin 13 via redundant recognition of each SNARE by an AP-3–BLOC-1 super-complex.
Chandrakumar et al. reveal that lumen formation in epithelial cells is regulated by ADP-ribosylation and ubiquitylation. Tankyrase inhibits its substrates SH3BP5 and SH3BP5L, which are Rab11a guanine nucleotide exchange factors, while the E3 ligase RNF146 promotes Rab11a activity by degrading Tankyrase during lumenogenesis.
EGFR endocytosis is triggered by ligand binding or activation of p38 MAPK. Perez Verdaguer et al. elucidate phosphorylation-dependent mechanisms of p38-induced endocytosis of EGFR and dissect the interplay between ligand- and p38-induced clathrin-mediated and clathrin-independent pathways of EGFR endocytosis.
This study shows that Rab40b interacts with Cullin5 and that loss of Rab40b–Cullin5 binding affects stress fiber formation and focal adhesion dynamics. Mechanistically, these effects are mediated in part by EPLIN, which is a target for Rab40b–Cullin5-dependent localized ubiquitylation and degradation.
Nakayama et al. show that Daple is responsible for the increased microtubule (MT) density on the Frizzled side of the apical junctional complex (AJC) in multiciliated cells via bundling and stabilizing MTs and mediating interactions between MTs and the AJC.
Badmos et al. find that the deubiquitinating enzyme nonstop/USP22 is essential for collective migration of Drosophila border cells. In this context, nonstop regulates the expression of hippo signaling pathway components, localization of polarity determinants, and polarization of the actin cytoskeleton.
Yang et al. develop a proteomics-based approach to systematically isolate asymmetrically localized proteins in Dictyostelium, through which they identify an LRR domain–containing protein named Leep1. Their results reveal that the spatiotemporal coordination of PIP3 signaling, Leep1, and Scar/WAVE complex modulates protrusion morphogenesis at the leading edge of cells.
In myeloproliferative neoplasms, oncogenic transformation involves mutations in the ER chaperone calreticulin (CRT) that drive aberrant activation of the thrombopoietin receptor/myeloproliferative leukemia protein (Mpl). Venkatesan et al. here describe the molecular mechanism underlying mutant CRT-mediated constitutive activation of Mpl.
Deliz-Aguirre et al. examine the molecular dynamics of interleukin 1 receptor signaling. Receptor sensing of IL-1 triggers the oligomerization of MyD88 and formation of the Myddosome signaling complex. The formation of a MyD88 oligomer of a requisite size serves as a threshold to active downstream signaling.
Ali-Murthy et al. show that during Drosophila oogenesis, several nurse cell nuclei move into the oocyte through a channel that opens when nurse cells and oocyte transiently fuse, and that nuclear transfer/elimination is essential for oocyte maturation and embryonic viability.
Katoku-Kikyo et al. show that the circadian master regulators Per1 and Per2 control the efficiency of myoblast differentiation via Igf2 activation. This pathway creates a preferred circadian time window for myoblast differentiation in vitro and muscle regeneration in vivo.