Nature Cell Biology

COPII and the regulation of protein sorting in mammals.

Publication Date: 2012 Feb PMID: 22298048
Authors: Zanetti, G. - Pahuja, K. B. - Studer, S. - Shim, S. - Schekman, R.
Journal: Nat Cell Biol

post to: CiteULike

Increasing organismal healthspan by enhancing mitochondrial protein quality control.

Publication Date: 2012 Feb PMID: 22298047
Authors: Luce, K. - Osiewacz, H. D.
Journal: Nat Cell Biol

post to: CiteULike

Aggregation is key for chimeric monkeys.

Publication Date: 2012 Feb PMID: 22298046
Authors: Le Bot, N.
Journal: Nat Cell Biol

post to: CiteULike

A mitochondria-lysosome transport pathway.

Publication Date: 2012 Feb PMID: 22298045
Authors: Chenette, E. J.
Journal: Nat Cell Biol

post to: CiteULike

Controlling enteric nerve cell migration.

Publication Date: 2012 Feb PMID: 22298044
Authors: Rosenthal, C. K.
Journal: Nat Cell Biol

post to: CiteULike

Actin gets the oxidation treatment from Mical.

Publication Date: 2012 Feb PMID: 22298043
Authors: Zaromytidou, A. I.
Journal: Nat Cell Biol

post to: CiteULike

Ras hitchhikes on PDE6delta.

Publication Date: 2012 Feb PMID: 22298042
Authors: Philips, M. R.
Journal: Nat Cell Biol

Ras GTPases are tethered to cellular membranes by a farnesyl lipid that modifies a carboxy-terminal cysteine. One of the ways Ras traffics between membranes is via fluid-phase diffusion, suggesting that a cytosolic chaperone might be needed to shield the farnesyl lipid during transport. PDE6delta is now revealed to be a farnesyl-binding chaperone that facilitates the trafficking and signalling of Ras.

post to: CiteULike

Efficient generation of adipocytes in a dish.

Publication Date: 2012 Feb PMID: 22298041
Authors: Elefanty, A. G. - Stanley, E. G.
Journal: Nat Cell Biol

A protocol for efficient differentiation of human pluripotent stem cells into white and brown adipocytes now enables their detailed examination at a cellular and molecular level, facilitating the study of adipocyte dysfunction in a range of metabolic diseases including diabetes, heart disease and obesity.

post to: CiteULike

Stromal miR-320 keeps an oncogenic secretome in check.

Publication Date: 2012 Feb PMID: 22298040
Authors: Khew-Goodall, Y. - Goodall, G. J.
Journal: Nat Cell Biol

Cancer-associated fibroblasts contribute to malignancy by expressing secreted pro-tumorigenic molecules. The microRNA miR-320 is now shown to be a crucial component of a PTEN-controlled tumour-suppressive axis in stromal fibroblasts. Loss of PTEN and miR-320 induces an oncogenic secretome that reprogrammes the tumour microenvironment to promote invasion and angiogenesis.

post to: CiteULike

Emerging functions of the VCP/p97 AAA-ATPase in the ubiquitin system.

Publication Date: 2012 Feb PMID: 22298039
Authors: Meyer, H. - Bug, M. - Bremer, S.
Journal: Nat Cell Biol

The ATP-driven chaperone valosin-containing protein (VCP)/p97 governs critical steps in ubiquitin-dependent protein quality control and intracellular signalling pathways. It cooperates with diverse partner proteins to help process ubiquitin-labelled proteins for recycling or degradation by the proteasome in many cellular contexts. Recent studies have uncovered unexpected cellular functions for p97 in autophagy, endosomal sorting and regulating protein degradation at the outer mitochondrial membrane, and elucidated a role for p97 in key chromatin-associated processes. These findings extend the functional relevance of p97 to lysosomal degradation and reveal a surprising dual role in protecting cells from protein stress and ensuring genome stability during proliferation.

post to: CiteULike

Finding MyoD with a little help from my friends.

Publication Date: 2012 Feb PMID: 22298038
Authors: Lassar, A.
Journal: Nat Cell Biol

post to: CiteULike

On target: A public repository for large-scale RNAi experiments.

Publication Date: 2012 Feb PMID: 22298037
Authors: Shamu, C. E. - Wiemann, S. - Boutros, M.
Journal: Nat Cell Biol

post to: CiteULike

APC/C-mediated multiple monoubiquitylation provides an alternative degradation signal for cyclin B1.

Publication Date: 2012 Feb PMID: 22286100
Authors: Dimova, N. V. - Hathaway, N. A. - Lee, B. H. - Kirkpatrick, D. S. - Berkowitz, M. L. - Gygi, S. P. - Finley, D. - King, R. W.
Journal: Nat Cell Biol

The anaphase-promoting complex or cyclosome (APC/C) initiates mitotic exit by ubiquitylating cell-cycle regulators such as cyclin B1 and securin. Lys 48-linked ubiquitin chains represent the canonical signal targeting proteins for degradation by the proteasome, but they are not required for the degradation of cyclin B1. Lys 11-linked ubiquitin chains have been implicated in degradation of APC/C substrates, but the Lys 11-chain-forming E2 UBE2S is not essential for mitotic exit, raising questions about the nature of the ubiquitin signal that targets APC/C substrates for degradation. Here we demonstrate that multiple monoubiquitylation of cyclin B1, catalysed by UBCH10 or UBC4/5, is sufficient to target cyclin B1 for destruction by the proteasome. When the number of ubiquitylatable lysines in cyclin B1 is restricted, Lys 11-linked ubiquitin polymers elaborated by UBE2S become increasingly important. We therefore explain how a substrate that contains multiple ubiquitin acceptor sites confers flexibility in the requirement for particular E2 enzymes in modulating the rate of ubiquitin-dependent proteolysis.

post to: CiteULike

The LIMD1 protein bridges an association between the prolyl hydroxylases and VHL to repress HIF-1 activity.

Publication Date: 2012 Feb PMID: 22286099
Authors: Foxler, D. E. - Bridge, K. S. - James, V. - Webb, T. M. - Mee, M. - Wong, S. C. - Feng, Y. - Constantin-Teodosiu, D. - Petursdottir, T. E. - Bjornsson, J. - Ingvarsson, S. - Ratcliffe, P. J. - Longmore, G. D. - Sharp, T. V.
Journal: Nat Cell Biol

There are three prolyl hydroxylases (PHD1, 2 and 3) that regulate the hypoxia-inducible factors (HIFs), the master transcriptional regulators that respond to changes in intracellular O(2) tension. In high O(2) tension (normoxia) the PHDs hydroxylate two conserved proline residues on HIF-1alpha, which leads to binding of the von Hippel-Lindau (VHL) tumour suppressor, the recognition component of a ubiquitin-ligase complex, initiating HIF-1alpha ubiquitylation and degradation. However, it is not known whether PHDs and VHL act separately to exert their enzymatic activities on HIF-1alpha or as a multiprotein complex. Here we show that the tumour suppressor protein LIMD1 (LIM domain-containing protein) acts as a molecular scaffold, simultaneously binding the PHDs and VHL, thereby assembling a PHD-LIMD1-VHL protein complex and creating an enzymatic niche that enables efficient degradation of HIF-1alpha. Depletion of endogenous LIMD1 increases HIF-1alpha levels and transcriptional activity in both normoxia and hypoxia. Conversely, LIMD1 expression downregulates HIF-1 transcriptional activity in a manner depending on PHD and 26S proteasome activities. LIMD1 family member proteins Ajuba and WTIP also bind to VHL and PHDs 1 and 3, indicating that these LIM domain-containing proteins represent a previously unrecognized group of hypoxic regulators.

post to: CiteULike

Mitochondrial outer-membrane protein FUNDC1 mediates hypoxia-induced mitophagy in mammalian cells.

Publication Date: 2012 Feb PMID: 22267086
Authors: Liu, L. - Feng, D. - Chen, G. - Chen, M. - Zheng, Q. - Song, P. - Ma, Q. - Zhu, C. - Wang, R. - Qi, W. - Huang, L. - Xue, P. - Li, B. - Wang, X. - Jin, H. - Wang, J. - Yang, F. - Liu, P. - Zhu, Y. - Sui, S. - Chen, Q.
Journal: Nat Cell Biol

Accumulating evidence has shown that dysfunctional mitochondria can be selectively removed by mitophagy. Dysregulation of mitophagy is implicated in the development of neurodegenerative disease and metabolic disorders. How individual mitochondria are recognized for removal and how this process is regulated remain poorly understood. Here we report that FUNDC1, an integral mitochondrial outer-membrane protein, is a receptor for hypoxia-induced mitophagy. FUNDC1 interacted with LC3 through its typical LC3-binding motif Y(18)xxL(21), and mutation of the LC3-interaction region impaired its interaction with LC3 and the subsequent induction of mitophagy. Knockdown of endogenous FUNDC1 significantly prevented hypoxia-induced mitophagy, which could be reversed by the expression of wild-type FUNDC1, but not LC3-interaction-deficient FUNDC1 mutants. Mechanistic studies further revealed that hypoxia induced dephosphorylation of FUNDC1 and enhanced its interaction with LC3 for selective mitophagy. Our findings thus offer insights into mitochondrial quality control in mammalian cells.

post to: CiteULike

Endocytosis by Numb breaks Notch symmetry at cytokinesis.

Publication Date: 2012 Feb PMID: 22267085
Authors: Couturier, L. - Vodovar, N. - Schweisguth, F.
Journal: Nat Cell Biol

Cell-fate diversity can be generated by the unequal segregation of the Notch regulator Numb at mitosis in both vertebrates and invertebrates. Whereas the mechanisms underlying unequal inheritance of Numb are understood, how Numb antagonizes Notch has remained unsolved. Live imaging of Notch in sensory organ precursor cells revealed that nuclear Notch is detected at cytokinesis in the daughter cell that does not inherit Numb. Numb and Sanpodo act together to regulate Notch trafficking and establish directional Notch signalling at cytokinesis. We propose that unequal segregation of Numb results in increased endocytosis in one daughter cell, hence asymmetry of Notch at the cytokinetic furrow, directional signalling and binary fate choice.

post to: CiteULike

Programming human pluripotent stem cells into white and brown adipocytes.

Publication Date: 2012 Feb PMID: 22246346
Authors: Ahfeldt, T. - Schinzel, R. T. - Lee, Y. K. - Hendrickson, D. - Kaplan, A. - Lum, D. H. - Camahort, R. - Xia, F. - Shay, J. - Rhee, E. P. - Clish, C. B. - Deo, R. C. - Shen, T. - Lau, F. H. - Cowley, A. - Mowrer, G. - Al-Siddiqi, H. - Nahrendorf, M. - Musunuru, K. - Gerszten, R. E. - Rinn, J. L. - Cowan, C. A.
Journal: Nat Cell Biol

The utility of human pluripotent stem cells is dependent on efficient differentiation protocols that convert these cells into relevant adult cell types. Here we report the robust and efficient differentiation of human pluripotent stem cells into white or brown adipocytes. We found that inducible expression of PPARG2 alone or combined with CEBPB and/or PRDM16 in mesenchymal progenitor cells derived from pluripotent stem cells programmed their development towards a white or brown adipocyte cell fate with efficiencies of 85%-90%. These adipocytes retained their identity independent of transgene expression, could be maintained in culture for several weeks, expressed mature markers and had mature functional properties such as lipid catabolism and insulin-responsiveness. When transplanted into mice, the programmed cells gave rise to ectopic fat pads with the morphological and functional characteristics of white or brown adipose tissue. These results indicate that the cells could be used to faithfully model human disease.

post to: CiteULike

Toll-like receptor activation suppresses ER stress factor CHOP and translation inhibition through activation of eIF2B.

Publication Date: 2012 Feb PMID: 22231169
Authors: Woo, C. W. - Kutzler, L. - Kimball, S. R. - Tabas, I.
Journal: Nat Cell Biol

Activation of Toll-like receptors (TLRs) induces the endoplasmic reticulum (ER) unfolded protein response (UPR) to accommodate essential protein translation. However, despite increased levels of phosphorylated eIF2alpha (p-eIF2alpha), a TLR-TRIF-dependent pathway assures that the cells avoid CHOP induction, apoptosis and translational suppression of critical proteins. As p-eIF2alpha decreases the functional interaction of eIF2 with eIF2B, a guanine nucleotide exchange factor (GEF), we explored the hypothesis that TLR-TRIF signalling activates eIF2B GEF activity to counteract the effects of p-eIF2alpha. We now show that TLR-TRIF signalling activates eIF2B GEF through PP2A-mediated serine dephosphorylation of the eIF2B varepsilon-subunit. PP2A itself is activated by decreased Src-family-kinase-induced tyrosine phosphorylation of its catalytic subunit. Each of these processes is required for TLR-TRIF-mediated CHOP suppression in ER-stressed cells in vitro and in vivo. Thus, in the setting of prolonged, physiologic ER stress, a unique TLR-TRIF-dependent translational control pathway enables cells to carry out essential protein synthesis and avoid CHOP-induced apoptosis while still benefiting from the protective arms of the UPR.

post to: CiteULike

Multicilin promotes centriole assembly and ciliogenesis during multiciliate cell differentiation.

Publication Date: 2012 Feb PMID: 22231168
Authors: Stubbs, J. L. - Vladar, E. K. - Axelrod, J. D. - Kintner, C.
Journal: Nat Cell Biol

Multiciliate cells function prominently in the respiratory system, brain ependyma and female reproductive tract to produce vigorous fluid flow along epithelial surfaces. These specialized cells form during development when epithelial progenitors undergo an unusual form of ciliogenesis, in which they assemble and project hundreds of motile cilia. Notch inhibits multiciliate cell formation in diverse epithelia, but how progenitors overcome lateral inhibition and initiate multiciliate cell differentiation is unknown. Here we identify a coiled-coil protein, termed multicilin, which is regulated by Notch and highly expressed in developing epithelia where multiciliate cells form. Inhibiting multicilin function specifically blocks multiciliate cell formation in Xenopus skin and kidney, whereas ectopic expression induces the differentiation of multiciliate cells in ectopic locations. Multicilin localizes to the nucleus, where it directly activates the expression of genes required for multiciliate cell formation, including foxj1 and genes mediating centriole assembly. Multicilin is also necessary and sufficient to promote multiciliate cell differentiation in mouse airway epithelial cultures. These findings indicate that multicilin initiates multiciliate cell differentiation in diverse tissues, by coordinately promoting the transcriptional changes required for motile ciliogenesis and centriole assembly.

post to: CiteULike