April 2017 | Volume 216, No. 4
People & Ideas
- Neurons eat glutamate to stay alive
Fendt and Verstreken preview work from Divakaruni et al. indicating that neurons can undergo metabolic changes to rely on glutamate for energy production, limiting excitotoxic injury.
- Tensin links energy metabolism to extracellular matrix assembly
Dornier and Norman discuss the findings by Georgiadou et al. that show that AMPK activity regulates tensin expression, thereby modulating α5β1-integrin and fibrillar adhesion assembly.
- Macrophages: micromanagers of antagonistic signaling nanoclusters
Eggeling and Davis discuss work by Lopes et al. demonstrating how macrophages integrate antagonistic signaling events via receptor reorganization.
- Telomere-driven diseases and telomere-targeting therapies
Martínez and Blasco review the molecular mechanisms underlying diseases associated with telomere dysfunction, including telomeropathies, age-related disorders, and cancer. Current and future therapeutic strategies to treat and prevent these diseases, including preclinical development of telomere-targeted therapies using mouse models, are discussed.
- The MICOS component Mic60 displays a conserved membrane-bending activity that is necessary for normal cristae morphology
The multisubunit mitochondrial contact site and cristae organizing system (MICOS) plays an important role in cristae junction formation. Tarasenko et al. show that the MICOS component Mic60 actively bends membranes and that this activity is evolutionarily conserved and necessary for cristae structure.
- TANGO1 assembles into rings around COPII coats at ER exit sites
TANGO1 interacts with COPII components to generate a transport carrier for export of large cargo from the endoplasmic reticulum. Raote et al. show that TANGO1 molecules assemble to form a closed ribbon structure that encircles COPII components.
- An engineered minimal chromosomal passenger complex reveals a role for INCENP/Sli15 spindle association in chromosome biorientation
The chromosomal passenger complex (CPC), which includes the Aurora B kinase and the scaffold Sli15/INCENP, promotes chromosome biorientation. Fink et al. engineer a minimal CPC construct made of Aurora B and Sli15/INCENP and determine how specific protein domains contribute to chromosome biorientation.
- Dual recognition of chromatin and microtubules by INCENP is important for mitotic progression
The chromosomal passenger complex contributes to the activation of the mitotic checkpoint and is composed of INCENP, Survivin, Borealin, and the kinase Aurora B. Wheelock et al. define the role of the INCENP domains binding chromatin and microtubules in the mitotic checkpoint.
- Molecular mechanism of dynein recruitment to kinetochores by the Rod–Zw10–Zwilch complex and Spindly
The dynein motor is recruited to the kinetochore to capture spindle microtubules and control the spindle assembly checkpoint. Gama et al. reveal the molecular mechanism of how the Rod–Zw10–Zwilch complex and Spindly mediate dynein recruitment in Caenorhabditis elegans and human cells.
- Structure of the RZZ complex and molecular basis of its interaction with Spindly
The Rod–Zw10–Zwilch (RZZ) complex assembles as a fibrous corona on kinetochores before microtubule attachment during mitotic spindle formation. Mosalaganti et al. provide new structural insight into the Spindly–RZZ complex that suggests that it resembles a dynein adaptor–cargo pair in the kinetochore corona.
- Structural analysis of the role of TPX2 in branching microtubule nucleation
TPX2 is required for microtubule nucleation in mitosis, but the mechanism underlying its function is unclear. Alfaro-Aco et al. analyze the domains of TPX2 necessary for its activity and identify the minimal region required for branching microtubule nucleation.
- KDM3A coordinates actin dynamics with intraflagellar transport to regulate cilia stability
Yeyati et al. demonstrate that the histone demethylase KDM3A acts as a negative regulator of ciliogenesis by modulating actin dynamics, both transcriptionally and by directly binding actin. KDM3A influences local actin networks to restrict intraflagellar transport during ciliogenesis; in its absence, cilia become unstable with abnormal lengths and accumulated intraflagellar transport proteins.
- FUS inclusions disrupt RNA localization by sequestering kinesin-1 and inhibiting microtubule detyrosination
Amyotrophic lateral sclerosis–associated mutations promote the formation of cytoplasmic FUS inclusions. In this study, Yasuda et al. show in fibroblasts and neurons that kinesin-1 is sequestered in FUS inclusions, resulting in a loss of detyrosinated microtubules and mislocalization of specific RNAs.
- Tango1 spatially organizes ER exit sites to control ER export
Drosophila melanogaster Tango1 is required for secretion of Collagen IV. Liu et al. use a genetic analysis to show that Tango1 is required to spatially maintain the size and integrity of ER exit site–Golgi units and that loss of Tango1 function impairs not only Collagen IV secretion but also general secretion.
- The Rab7 effector PLEKHM1 binds Arl8b to promote cargo traffic to lysosomes
Rab7 and Arl8b mediate vesicle transport and fusion with lysosomes. Marwaha et al. show that the Rab7 effector PLEKHM1 competes with PLEKHM2/SKIP for binding to Arl8b and that Arl8 mediates recruitment of the HOPS complex to PLEKHM1-positive vesicles for fusion, suggesting that Arl8b and its effectors orchestrate lysosomal transport and fusion.
- Chlamydia preserves the mitochondrial network necessary for replication via microRNA-dependent inhibition of fission
Chlamydiae are intracellular pathogens that depend on the host for their survival and development. Chowdhury et al. demonstrate that Chlamydia trachomatis infection can prevent mitochondrial fission in primary cells by reducing DRP1 abundance via miR-30c–dependent inhibition of p53.
- Inhibition of the mitochondrial pyruvate carrier protects from excitotoxic neuronal death
In cortical neurons and hippocampal slice cultures, blocking mitochondrial pyruvate uptake rewires metabolism to increase reliance on glutamate to fuel the TCA cycle. This diminishes the readily releasable pool of neuronal glutamate and minimizes the positive-feedback cascade of excitotoxic injury.
- AMPK negatively regulates tensin-dependent integrin activity
Georgiadou et al. show that the major metabolic sensor AMPK regulates integrin activity and integrin-dependent processes in fibroblasts by modulating tensin levels. Loss of AMPK up-regulates tensin expression, triggering enhanced integrin activity in fibrillar adhesions, fibronectin remodeling, and traction stress.
- Membrane nanoclusters of FcγRI segregate from inhibitory SIRPα upon activation of human macrophages
Lopes et al. use superresolution microscopy to visualize the nanoscale organization of activating and inhibitory receptors on human macrophages. Nanoclusters of inhibitory SIRPα and activating FcγRI associate in the cell’s resting state, but engagement of FcγRI induces their segregation.
- ELKS1 localizes the synaptic vesicle priming protein bMunc13-2 to a specific subset of active zones
Munc13 proteins are key regulators of neurotransmitter release at presynaptic active zones. Kawabe et al. describe a molecular mechanism by which the active zone protein ELKS1 recruits a functionally unique Munc13 isoform, bMunc13-2, to a defined subset of synapses.
- Unique spectral signatures of the nucleic acid dye acridine orange can distinguish cell death by apoptosis and necroptosis
Plemel et al. use a spectrally sensitive nucleic acid dye, acridine orange, to demonstrate a loss of RNA early during cell death. Acridine orange can also be used to distinguish apoptosis from necrosis/necroptosis in vitro and in fixed tissue samples.
- Raft-based sphingomyelin interactions revealed by new fluorescent sphingomyelin analogs
The behavior of sphingomyelin (SM) in the plasma membrane is unclear. Using new fluorescent SM analogs and single-molecule tracking, Kinoshita et al. find that SM transiently and continually interacts with the glycosylphosphatidylinositol (GPI)-anchored protein CD59 in oligomer size–, cholesterol-, and GPI anchoring–dependent manners.