Rhes travels from cell to cell and transports Huntington disease protein via TNT-like protrusion
Tunneling nanotubes (TNT) are thin, membranous, tunnel-like cell-to-cell connections, but the mechanisms underlying their biogenesis or functional role remains obscure. Here, we report, Rhes, a brain-enriched GTPase/SUMO E3-like protein, induces the biogenesis of TNT-like cellular protrusions, "Rhes tunnels," through which Rhes moves from cell to cell and transports Huntington disease (HD) protein, the poly-Q expanded mutant Huntingtin (mHTT). The formation of TNT-like Rhes tunnels requires the Rhes’s serine 33, C-terminal CAAX, and a SUMO E3-like domain. Electron microscopy analysis revealed that TNT-like Rhes tunne...
Source: Journal of Cell Biology - June 2, 2019 Category: Cytology Authors: Sharma, M., Subramaniam, S. Tags: Disease, Cell Signaling Articles Source Type: research
PAK2 links cell survival to mechanotransduction and metabolism
Too little or too much force can trigger cell death, yet factors that ensure the survival of cells remain largely unknown. Here, we demonstrate that E-cadherin responds to force by recruiting and activating p21-activated protein kinase 2 (PAK2) to allow cells to stiffen, metabolize, and survive. Interestingly, PAK2 activation and its control of the apoptotic response are specific for the amplitude of force applied. Specifically, under low amplitudes of physiological force, PAK2 is protected from proteolysis, thereby ensuring cell survival. In contrast, under higher amplitudes of physiological force, PAK2 is left unprotecte...
Source: Journal of Cell Biology - June 2, 2019 Category: Cytology Authors: Campbell, H. K., Salvi, A. M., OBrien, T., Superfine, R., DeMali, K. A. Tags: Adhesion, Cell Signaling, Biochemistry Articles Source Type: research
The PHLPP2 phosphatase is a druggable driver of prostate cancer progression
Metastatic prostate cancer commonly presents with targeted, bi-allelic mutations of the PTEN and TP53 tumor suppressor genes. In contrast, however, most candidate tumor suppressors are part of large recurrent hemizygous deletions, such as the common chromosome 16q deletion, which involves the AKT-suppressing phosphatase PHLPP2. Using RapidCaP, a genetically engineered mouse model of Pten/Trp53 mutant metastatic prostate cancer, we found that complete loss of Phlpp2 paradoxically blocks prostate tumor growth and disease progression. Surprisingly, we find that Phlpp2 is essential for supporting Myc, a key driver of lethal pr...
Source: Journal of Cell Biology - June 2, 2019 Category: Cytology Authors: Nowak, D. G., Katsenelson, K. C., Watrud, K. E., Chen, M., Mathew, G., DAndrea, V. D., Lee, M. F., Swamynathan, M. M., Casanova-Salas, I., Jibilian, M. C., Buckholtz, C. L., Ambrico, A. J., Pan, C.-H., Wilkinson, J. E., Newton, A. C., Trotman, L. C. Tags: Cell Signaling, Cancer Articles Source Type: research
Mutant p53 amplifies a dynamin-1/APPL1 endosome feedback loop that regulates recycling and migration
We report that dynamin-1 (Dyn1) is up-regulated at both the mRNA and protein levels in a manner dependent on expression of GOF mutant p53. Dyn1 is required for the recruitment and accumulation of the signaling scaffold, APPL1, to a spatially localized subpopulation of endosomes at the cell perimeter. We developed new tools to quantify peripherally localized early endosomes and measure the rapid recycling of integrins. We report that these perimeter APPL1 endosomes modulate Akt signaling and activate Dyn1 to create a positive feedback loop required for rapid recycling of EGFR and β1 integrins, increased focal adhesion ...
Source: Journal of Cell Biology - June 2, 2019 Category: Cytology Authors: Lakoduk, A. M., Roudot, P., Mettlen, M., Grossman, H. M., Schmid, S. L., Chen, P.-H. Tags: Cell Signaling, Trafficking, Cancer Articles Source Type: research
Rab5-dependent autophagosome closure by ESCRT
In the conserved autophagy pathway, autophagosomes (APs) engulf cellular components and deliver them to the lysosome for degradation. Before fusing with the lysosome, APs have to close via an unknown mechanism. We have previously shown that the endocytic Rab5-GTPase regulates AP closure. Therefore, we asked whether ESCRT, which catalyzes scission of vesicles into late endosomes, mediates the topologically similar process of AP sealing. Here, we show that depletion of representative subunits from all ESCRT complexes causes late autophagy defects and accumulation of APs. Focusing on two subunits, we show that Snf7 and the Vp...
Source: Journal of Cell Biology - June 2, 2019 Category: Cytology Authors: Zhou, F., Wu, Z., Zhao, M., Murtazina, R., Cai, J., Zhang, A., Li, R., Sun, D., Li, W., Zhao, L., Li, Q., Zhu, J., Cong, X., Zhou, Y., Xie, Z., Gyurkovska, V., Li, L., Huang, X., Xue, Y., Chen, L., Xu, H., Xu, H., Liang, Y., Segev, N. Tags: Cell Death and Autophagy, Genetics Articles Source Type: research
Somatic autophagy of axonal mitochondria in ischemic neurons
Mitophagy protects against ischemic neuronal injury by eliminating damaged mitochondria, but it is unclear how mitochondria in distal axons are cleared. We find that oxygen and glucose deprivation-reperfusion reduces mitochondrial content in both cell bodies and axons. Axonal mitochondria elimination was not abolished in Atg7fl/fl;nes-Cre neurons, suggesting the absence of direct mitophagy in axons. Instead, axonal mitochondria were enwrapped by autophagosomes in soma and axon-derived mitochondria prioritized for elimination by autophagy. Intriguingly, axonal mitochondria showed prompt loss of anterograde motility but incr...
Source: Journal of Cell Biology - June 2, 2019 Category: Cytology Authors: Zheng, Y., Zhang, X., Wu, X., Jiang, L., Ahsan, A., Ma, S., Xiao, Z., Han, F., Qin, Z.-H., Hu, W., Chen, Z. Tags: Disease, Cell Death and Autophagy, Trafficking, Neuroscience Articles Source Type: research
Deacetylation of Miro1 by HDAC6 blocks mitochondrial transport and mediates axon growth inhibition
Inhibition of histone deacetylase 6 (HDAC6) was shown to support axon growth on the nonpermissive substrates myelin-associated glycoprotein (MAG) and chondroitin sulfate proteoglycans (CSPGs). Though HDAC6 deacetylates α-tubulin, we find that another HDAC6 substrate contributes to this axon growth failure. HDAC6 is known to impact transport of mitochondria, and we show that mitochondria accumulate in distal axons after HDAC6 inhibition. Miro and Milton proteins link mitochondria to motor proteins for axon transport. Exposing neurons to MAG and CSPGs decreases acetylation of Miro1 on Lysine 105 (K105) and decreases ax...
Source: Journal of Cell Biology - June 2, 2019 Category: Cytology Authors: Kalinski, A. L., Kar, A. N., Craver, J., Tosolini, A. P., Sleigh, J. N., Lee, S. J., Hawthorne, A., Brito-Vargas, P., Miller-Randolph, S., Passino, R., Shi, L., Wong, V. S. C., Picci, C., Smith, D. S., Willis, D. E., Havton, L. A., Schiavo, G., Giger, R. Tags: Cell Signaling, Trafficking, Neuroscience Articles Source Type: research
Respiratory chain inactivation links cartilage-mediated growth retardation to mitochondrial diseases
In childhood, skeletal growth is driven by transient expansion of cartilage in the growth plate. The common belief is that energy production in this hypoxic tissue mainly relies on anaerobic glycolysis and not on mitochondrial respiratory chain (RC) activity. However, children with mitochondrial diseases causing RC dysfunction often present with short stature, which indicates that RC activity may be essential for cartilage-mediated skeletal growth. To elucidate the role of the mitochondrial RC in cartilage growth and pathology, we generated mice with impaired RC function in cartilage. These mice develop normally until birt...
Source: Journal of Cell Biology - June 2, 2019 Category: Cytology Authors: Holzer, T., Probst, K., Etich, J., Auler, M., Georgieva, V. S., Bluhm, B., Frie, C., Heilig, J., Niehoff, A., Nüchel, J., Plomann, M., Seeger, J. M., Kashkar, H., Baris, O. R., Wiesner, R. J., Brachvogel, B. Tags: Articles Source Type: research
Structural basis for the nuclear import and export functions of the biportin Pdr6/Kap122
Importins ferry proteins into nuclei while exportins carry cargoes to the cytoplasm. In the accompanying paper in this issue (Vera Rodriguez et al. 2019. J. Cell Biol. https://doi.org/10.1083/jcb.201812091), we discovered that Pdr6 is a biportin that imports, e.g., the SUMO E2 ligase Ubc9 while depleting the translation factor eIF5A from the nuclear compartment. In this paper, we report the structures of key transport intermediates, namely, of the Ubc9•Pdr6 import complex, of the RanGTP•Pdr6 heterodimer, and of the trimeric RanGTP•Pdr6•eIF5A export complex. These revealed nonlinear transport signals, ch...
Source: Journal of Cell Biology - June 2, 2019 Category: Cytology Authors: Aksu, M., Trakhanov, S., Vera Rodriguez, A., Görlich, D. Tags: Organelles, Trafficking, Biochemistry, Structural Biology Articles Source Type: research
Junctional tumor suppressors interact with 14-3-3 proteins to control planar spindle alignment
Proper orientation of the mitotic spindle is essential for cell fate determination, tissue morphogenesis, and homeostasis. During epithelial proliferation, planar spindle alignment ensures the maintenance of polarized tissue architecture, and aberrant spindle orientation can disrupt epithelial integrity. Nevertheless, in vivo mechanisms that restrict the mitotic spindle to the plane of the epithelium remain poorly understood. Here we show that the junction-localized tumor suppressors Scribbled (Scrib) and Discs large (Dlg) control planar spindle orientation via Mud and 14-3-3 proteins in the Drosophila wing disc epithelium...
Source: Journal of Cell Biology - June 2, 2019 Category: Cytology Authors: Nakajima, Y.-i., Lee, Z. T., McKinney, S. A., Swanson, S. K., Florens, L., Gibson, M. C. Tags: Cell Cycle and Division, Polarity, Development Articles Source Type: research
Retargeting of macroH2A following mitosis to cytogenetic-scale heterochromatic domains
The heritability of chromatin states through cell division is a potential contributor to the epigenetic maintenance of cellular memory of prior states. The macroH2A histone variant has properties of a regulator of epigenetic cell memory, including roles controlling gene silencing and cell differentiation. Its mechanisms of regional genomic targeting and maintenance through cell division are unknown. Here, we combined in vivo imaging with biochemical and genomic approaches to show that human macroH2A is incorporated into chromatin in the G1 phase of the cell cycle following DNA replication. The newly incorporated macroH2A r...
Source: Journal of Cell Biology - June 2, 2019 Category: Cytology Authors: Sato, H., Wu, B., Delahaye, F., Singer, R. H., Greally, J. M. Tags: Chromatin or Epigenetics, Genetics Articles Source Type: research
Rap1 binding and a lipid-dependent helix in talin F1 domain promote integrin activation in tandem
Rap1 GTPases bind effectors, such as RIAM, to enable talin1 to induce integrin activation. In addition, Rap1 binds directly to the talin1 F0 domain (F0); however, this interaction makes a limited contribution to integrin activation in CHO cells or platelets. Here, we show that talin1 F1 domain (F1) contains a previously undetected Rap1-binding site of similar affinity to that in F0. A structure-guided point mutant (R118E) in F1, which blocks Rap1 binding, abolishes the capacity of Rap1 to potentiate talin1-induced integrin activation. The capacity of F1 to mediate Rap1-dependent integrin activation depends on a unique loop...
Source: Journal of Cell Biology - June 2, 2019 Category: Cytology Authors: Gingras, A. R., Lagarrigue, F., Cuevas, M. N., Valadez, A. J., Zorovich, M., McLaughlin, W., Lopez-Ramirez, M. A., Seban, N., Ley, K., Kiosses, W. B., Ginsberg, M. H. Tags: Adhesion, Cell Signaling, Biochemistry Reports Source Type: research
ATG2 transports lipids to promote autophagosome biogenesis
During macroautophagic stress, autophagosomes can be produced continuously and in high numbers. Many different organelles have been reported as potential donor membranes for this sustained autophagosome growth, but specific machinery to support the delivery of lipid to the growing autophagosome membrane has remained unknown. Here we show that the autophagy protein, ATG2, without a clear function since its discovery over 20 yr ago, is in fact a lipid-transfer protein likely operating at the ER–autophagosome interface. ATG2A can bind tens of glycerophospholipids at once and transfers lipids robustly in vitro. An N-term...
Source: Journal of Cell Biology - June 2, 2019 Category: Cytology Authors: Valverde, D. P., Yu, S., Boggavarapu, V., Kumar, N., Lees, J. A., Walz, T., Reinisch, K. M., Melia, T. J. Tags: Cell Death and Autophagy, Membrane and Lipid Biology Reports Source Type: research
Post-translational regulation of ubiquitin signaling
Ubiquitination regulates many essential cellular processes in eukaryotes. This post-translational modification (PTM) is typically achieved by E1, E2, and E3 enzymes that sequentially catalyze activation, conjugation, and ligation reactions, respectively, leading to covalent attachment of ubiquitin, usually to lysine residues of substrate proteins. Ubiquitin can also be successively linked to one of the seven lysine residues on ubiquitin to form distinctive forms of polyubiquitin chains, which, depending upon the lysine used and the length of the chains, dictate the fate of substrate proteins. Recent discoveries revealed th...
Source: Journal of Cell Biology - June 2, 2019 Category: Cytology Authors: Song, L., Luo, Z.-Q. Tags: Cell Signaling, Biochemistry Review Source Type: research
Bayonets over bombs: RIPK3 and MLKL restrict Listeria without triggering necroptosis
RIPK3 induces necroptosis by phosphorylating MLKL, which then induces plasma membrane rupture and necrotic cell death. In this issue, Sai et al. (2019. J. Cell Biol. https://doi.org/10.1083/jcb.201810014) show that RIPK3-MLKL signaling in epithelial cells promotes Listeria clearance by directly suppressing cytosolic bacterial replication, without activating cell death. (Source: Journal of Cell Biology)
Source: Journal of Cell Biology - June 2, 2019 Category: Cytology Authors: Zhang, T., Balachandran, S. Tags: Spotlight Source Type: research
