March 2017 | Volume 216, No. 3
People & Ideas
- Fragile phagocytes: FMRP positively regulates engulfment activity
Logan highlights O’Conner et al.’s discovery that the Fragile X mental retardation protein gene is a key requirement for phagocytosis.
- A game of musical chairs: Pro- and anti-resection factors compete for TOPBP1 binding after DNA damage
Shimada and Gasser discuss new findings from the Smolka laboratory supporting a competitive model for nonhomologous end joining and homologous recombination factors at DNA breaks.
- The peroxisomes strike BAK: Regulation of peroxisome integrity by the Bcl-2 family
Chipuk and Luna-Vargas discuss Hosoi et al.’s study revealing conserved regulation of mitochondrial and peroxisome membrane permeabilization by the Bcl2 family.
- The heat shock factor HSF1 juggles protein quality control and metabolic regulation
Cantó previews work by Qiao et al. linking the heat shock factor HSF1 to metabolic control independently of proteostatic regulation.
- eIF2α links mitochondrial dysfunction to dendritic degeneration
Xin Qi previews work by Tsuyama and colleagues linking eIF2α phosphorylation-mediated control of translation with neuronal subtype-specific mitochondrial stress-induced dendritic branching defects.
- Patterned cell and matrix dynamics in branching morphogenesis
Wang et al. discuss the intricate processes required during embryogenesis for the formation of the branched architecture of organs such as the lung, kidney, and blood vessels.
- Arabidopsis HAP2/GCS1 is a gamete fusion protein homologous to somatic and viral fusogens
HAP2/GCS1 is essential for gamete fusion in plants, invertebrates, and protists. Valansi et al. demonstrate that a plant HAP2 is an authentic fusion protein that can fuse animal cells.
- Mycobacterium tuberculosis replicates within necrotic human macrophages
Mycobacterium tuberculosis triggers macrophage cell death by necrosis, but it is unclear how this affects bacterial replication. Lerner et al. show that this pathogen replicates within necrotic human macrophages before disseminating to other cells upon loss of plasma membrane integrity.
- A Drosophila model of Fragile X syndrome exhibits defects in phagocytosis by innate immune cells
Recent evidence suggests that Fragile X syndrome and other types of autism are associated with immune system defects. Here, O’Connor et al. find that Drosophila Fmr1 mutants, a model for Fragile X syndrome, exhibit defects in phagocytosis by innate immune cells in both the body and the brain.
- Human centromeric CENP-A chromatin is a homotypic, octameric nucleosome at all cell cycle points
In this study, the authors use new reference models for 23 human centromeres and find that at all cell cycle phases centromeric CENP-A chromatin complexes are octameric nucleosomes with two molecules of CENP-A. This finding refutes previous models that have suggested that hemisomes may briefly transition to octameric nucleosomes.
- TOPBP1Dpb11 plays a conserved role in homologous recombination DNA repair through the coordinated recruitment of 53BP1Rad9
The scaffold protein TOPBP1Dpb11 has been implicated in homologous recombination DNA repair, but its function and mechanism of action remain unclear. Liu et al. define a conserved role for TOPBP1Dpb11 in recombination control through regulated, opposing interactions with pro- and anti-resection factors.
- The nuclear transport receptor Importin-11 is a tumor suppressor that maintains PTEN protein
Reduced PTEN protein is linked to tumorigenesis. Here, Chen et al. show that the nuclear transport receptor Importin-11 separates PTEN from degradation machinery. IPO11 mutant mice exhibit PTEN degradation, lung adenocarcinoma, and prostate neoplasia. In human prostatectomy patients, IPO11 status predicts disease recurrence and metastasis.
- TorsinA controls TAN line assembly and the retrograde flow of dorsal perinuclear actin cables during rearward nuclear movement
In fibroblasts and myoblasts polarizing for migration, retrograde actin flow moves the nucleus rearward, orienting the centrosome toward the leading edge. The nucleus engages moving dorsal actin cables through linear arrays of nesprin-2G and SUN2 called TAN lines. In this study, Saunders et al. report that the nuclear envelope–localized AAA+ ATPase torsinA and its activator, LAP1, are required for TAN line assembly and retrograde dorsal actin cable flow.
- CLUH regulates mitochondrial metabolism by controlling translation and decay of target mRNAs
CLUH binds mRNAs implicated in intermediate metabolism and oxidative phosphorylation, but the physiological and molecular significance of these interactions is unclear. Schatton et al. use new constitutive and liver-specific Cluh knockouts to define the function of CLUH in catabolic and energy-converting pathways as a regulator of the translation and stability of target mRNAs.
- Cardiolipin promotes electron transport between ubiquinone and complex I to rescue PINK1 deficiency
Parkinson’s disease–causing mutations in PINK1 yield mitochondrial defects including inefficient electron transport between complex I and ubiquinone. Vos et al. show that genetic and pharmacological inhibition of fatty acid synthase bypass these complex I defects in fly, mouse, and human Parkinson’s disease models.
- The VDAC2–BAK axis regulates peroxisomal membrane permeability
VDAC2 controls the stable localization of BAK to mitochondria and its ability to mediate mitochondrial outer membrane permeabilization. Hosoi et al. now report that BAK shifts from mitochondria to peroxisomes under VDAC2-deficient conditions, giving rise to the mislocalization of peroxisomal matrix proteins such as catalase, which suggests that BAK can also regulate the permeability of peroxisomal membranes.
- The transcriptional regulator of the chaperone response HSF1 controls hepatic bioenergetics and protein homeostasis
How cells sense energetic demands and regulate their bioenergetic networks to balance anabolism and catabolism is unclear. Qiao et al show that HSF1, a regulator of the chaperone response, has a central role in systemic energy sensing and is required for metabolic adaptation to nutrient availability.
- Tubby family proteins are adapters for ciliary trafficking of integral membrane proteins
Trafficking of integral membrane proteins to cilia is poorly understood. Badgandi et al. show that tubby family proteins TULP3 and TUB act as general adapters for ciliary trafficking of structurally diverse integral membrane cargo like GCPRs and the polycystin 1/2 complex.
- Osteoblastic Lrp4 promotes osteoclastogenesis by regulating ATP release and adenosine-A2AR signaling
Lrp4 is mutated in patients with high-bone-mass diseases. Loss of Lrp4 in osteoblasts (OBs) increases bone formation by OBs and decreases bone resorption by osteoclasts through an unclear mechanism. Xiong et al. show that overproduction of extracellular adenosine in Lrp4-deficient OBs, which are derived from ATP hydrolysis and signals through A2AR and RANK, may underlie Lrp4 regulation of osteoclastogenesis.
- Transcriptional determinants of tolerogenic and immunogenic states during dendritic cell maturation
Dendritic cells promote either immunosuppressive or immunogenic T cell responses, but the transcriptional and epigenetic programs regulating these functions are unclear. Vander Lugt et al. dissect the distinct programs underlying the immunogenic and tolerogenic mature states of dendritic cells in vitro.
- Differential roles of α-, β-, and γ-actin in axon growth and collateral branch formation in motoneurons
α-, β-, and γ-actin differentially regulate cytoskeletal dynamics and stability in axons of motoneurons. Locally translated α-actin contributes to stable actin filaments in axonal branches, whereas β- and γ-actin give rise to highly dynamic filaments that modulate growth cone dynamics.
- Mitochondrial dysfunction induces dendritic loss via eIF2α phosphorylation
Mitochondrial dysfunction is associated with neuropathological events, but how it mediates loss of specific neuronal subtypes is unclear. Tsuyama et al. show that mitochondrial dysfunction triggers selective dendritic loss in class IV arborization neurons in a manner dependent on eIF2α phosphorylation and translation inhibition.
- VHL promotes immune response against renal cell carcinoma via NF-κB–dependent regulation of VCAM-1
Labrousse-Arias et al. show that VHL expression leads to increased VCAM-1 levels in renal cell carcinoma through an NF-κB–dependent mechanism that seems to contribute to the antitumoral immune response. This study also suggests that VCAM-1 levels might serve as a marker of ccRCC progression in human patients.