Autophagy and cell growth - the yin and yang of nutrient responses

Advance Online Publication May 30, 2012 doi: 10.1242/?jcs.103333 May 15, 2012 J Cell Sci 125, 2359-2368. Thomas P. Neufeld?

Department of Genetics, Cell Biology and Development, University of Minnesota, Minneapolis, MN 55455, USA neufeld{at}med.umn.edu As a response to nutrient deprivation and other cell stresses, autophagy is often induced in the context of reduced or arrested cell growth. A plethora of signaling molecules and pathways have been shown to have opposing effects on cell growth and autophagy, and results of recent functional screens on a genomic scale support the idea that these processes might represent mutually exclusive cell fates. Understanding the ways in which autophagy and cell growth relate to one another is becoming increasingly important, as new roles for autophagy in tumorigenesis and other growth-related phenomena are uncovered. This Commentary highlights recent findings that link autophagy and cell growth, and explores the mechanisms underlying these connections and their implications for cell physiology and survival. Autophagy and cell growth can inhibit one another through a variety of direct and indirect mechanisms, and can be independently regulated by common signaling pathways. The central role of the mammalian target of rapamycin (mTOR) pathway in regulating both autophagy and cell growth exemplifies one such mechanism. In addition, mTOR-independent signaling and other more direct connections between autophagy and cell growth will also be discussed.

Key words This article is part of a Minifocus on Autophagy. For further reading, please see related articles: ‘Ubiquitin-like proteins and autophagy at a glance’ by Tomer Shpilka et al. (J. Cell Sci. 125, 2343-2348) and ‘Autophagy and cancer – issues we need to digest’ by Emma Liu and Kevin Ryan (J. Cell Sci. 125, 2349-2358).

Funding

The work of our laboratory is supported by the National Institutes of Health [grant number GM62509]. Deposited in PMC for release after 12 months.

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Perilipin family members preferentially sequester to either triacylglycerol- or cholesteryl ester-specific intracellular lipid storage droplets

Advance Online Publication June 8, 2012 doi: 10.1242/?jcs.104943 Perilipin family proteins (Plins) coat the surface of intracellular neutral lipid storage droplets in various cell types. Studies across diverse species demonstrate that Plins regulate lipid storage metabolism through recruitment of lipases and other regulatory proteins to lipid droplet surfaces. Mammalian genomes encode 5 distinct Plin gene members and additional protein forms derive from specific mRNA splice variants. However, it is not known if the different Plins have distinct functional properties. Using biochemical, cellular imaging, and flow cytometric analyses, we now show that within individual cells of various types, the different Plin proteins preferentially sequester to separate pools of lipid storage droplets. By examining ectopically expressed GFP fusions and all endogenous Plin protein forms, we demonstrate that different Plins sequester to lipid droplets, comprised distinctly of either triacylcerides or of cholesterol esters. Further, Plins with strong association preferences to TAG (or CE) droplets can re-direct the relative intracellular TAG/CE balance toward the targeted lipid. Our data suggest diversity of Plin function, alter previous assumptions about shared collective actions of the Plins, and indicate that each Plin can have separate and unique functions.

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Regulation of apoptosis by Bat3-enhanced YWK-II protein/APLP2 stability

Advance Online Publication May 28, 2012 doi: 10.1242/?jcs.086553 YWK-II protein/APLP2 is a member of an evolutionarily conserved protein family that includes amyloid precursor protein (APP) and amyloid precursor like protein-1 (APLP1). We have previously demonstrated that YWK-II/APLP2 functions as a novel G0-protein-coupled receptor for Müllerian inhibiting substance (MIS) in cell survival. However, factors regulating the stability and turnover of YWK-II/APLP2 have not been identified. Here we present evidence that human leukocyte antigen-B-associated transcript 3 (Bat3), an important regulator involved in apoptosis, can interact with YWK-II/APLP2 and enhance its stability by reducing its ubiquitination and degradation by the ubiquitin-proteasome system. Co-expression of different Bat3 domain deletion constructs with YWK-II/APLP2 reveals that the proline-rich domain of Bat3 is required for its binding to YWK-II/APLP2. In addition, we find that the protein levels of YWK-II/APLP2 could be enhanced by nuclear export of Bat3 under apoptotic stimulation. We also find elevated levels of Bat3 and YWK-II/APLP2 in human colorectal cancer with a positive correlation between the two. Taken together, these results have revealed a previously undefined mechanism regulating cell apoptosis and suggest that aberrant enhancement of YWK-II/APLP2 by nuclear export of Bat3 may play a role in cancer development by inhibiting cell apoptosis.

This work was supported by grants from the National program for the Important Research Plan (2011CB944302, 2012CB944902/903), National Key Technology Support Program (2012BAI31B08), State Key Laboratory Special Fund (2060204), 111 Project (B08007) from Ministry of Education and the Focused Investment Scheme of The Chinese University of Hong Kong.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License, which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms.

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Heat shock induces rapid resorption of primary cilia

Advance Online Publication June 20, 2012 doi: 10.1242/?jcs.100545 Natalia V. Prodromou*, Clare Thompson*, Daniel P. S. Osborn, Kathryn F. Cogger, Rachel Ashworth, Martin M. Knight, Philip L. Beales and J. Paul Chapple?Correspondence: Dr Paul Chapple, Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK. Tel: +44 (0) 20 7882 6242; Fax +44 (0) 20 7882 6197; E-mail: j.p.chapple{at}qmul.ac.uk?*These authors contributed equally to this work

Primary cilia are involved in important developmental and disease pathways, such as regulation of neurogenesis and tumorigenesis. They function as sensory antennae and are essential in the regulation of key extracellular signalling systems. Here we investigate the effects of cell stress on primary cilia. Exposure of mammalian cells in vitro, and zebrafish cells in vivo, to elevated temperature resulted in the rapid loss of cilia by resorption. In mammalian cells cilia loss correlated with a reduction in hedgehog signalling. Heat shock dependent loss of cilia was decreased in cells where histone deacetylases (HDACs) were inhibited, suggesting resorption is mediated by the axoneme localised tubulin deacetylase HDAC6. In thermotolerant cells the rate of ciliary resorption was reduced. This implies a role for molecular chaperones in primary cilia maintenance. The cytosolic chaperone Hsp90 localises to the ciliary axoneme and its inhibition resulted in cilia loss. In the cytoplasm of unstressed cells, Hsp90 is known to exist in a complex with HDAC6. Moreover, immediately after heat shock Hsp90 levels were reduced in remaining cilia. We hypothesise ciliary resorption serves to attenuate cilia mediated signalling pathways in response to extracellular stress and that this mechanism is regulated in part by HDAC6 and Hsp90.

This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial Share Alike License, which permits unrestricted non-commercial use, distribution and reproduction in any medium provided that the original work is properly cited and all further distributions of the work or adaptation are subject to the same Creative Commons License terms.

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Semaphorin 3A elevates endothelial cell permeability through PP2A inactivation

Advance Online Publication June 8, 2012 doi: 10.1242/?jcs.108282 Armelle Le Guelte, Eva-Maria Galan-Moya, Julie Dwyer, Lucas Treps, Garance Kettler, Jagoda K. Hebda, Sonia Dubois, Cedric Auffray, Herve Chneiweiss, Nicolas Bidere and Julie Gavard*?*Correspondence: Julie Gavard, Institut Cochin 22 rue Mechain Rm. 306, 75014 Paris, France. Ph: +33 1 4051 6424; Fax: +33 1 4051 6430; e-mail: julie.gavard{at}inserm.frVE-cadherin-mediated cell-cell junction weakening increases paracellular permeability in response to both angiogenic and inflammatory stimuli. Although Semaphorin 3A has emerged as one of the few known anti-angiogenic factors to exhibit pro-permeability activity, little is known about how it triggers vascular leakage. Here we report that Semaphorin 3A induced VE-cadherin serine phosphorylation and internalization, cell-cell junction destabilization, and loss of barrier integrity in brain endothelial cells. In addition, high-grade glioma-isolated tumour initiating cells were found to secrete Semaphorin 3A, which promoted brain endothelial monolayer permeability. From a mechanistic standpoint, Semaphorin 3A impinged upon the basal activity of the serine phosphatase PP2A and disrupted PP2A interaction with VE-cadherin, leading to cell-cell junction disorganization and increased permeability. Accordingly, both pharmacological inhibition and siRNA-based knockdown of PP2A mimicked Semaphorin 3A effects on VE-cadherin. Hence, local Semaphorin 3A production impacts on the PP2A/VE-cadherin equilibrium and contributes to elevated vascular permeability.

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