Research Highlights |
Featured
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News & Views |
Mcl-1 rescues a glitch in the matrix
Bcl-2 family proteins are known to control cell death and influence mitochondrial function. The function of Mcl-1, an anti-apoptotic Bcl-2 protein, is now shown to depend on its subcellular localization. Mcl-1 at the mitochondrial outer membrane inhibits mitochondrial permeabilization to block apoptosis. However, a cleaved form of Mcl-1 localizes to the mitochondrial matrix and controls inner mitochondrial morphology and oxidative phosphorylation, without directly modulating apoptosis.
- Joshua L. Andersen
- & Sally Kornbluth
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Article |
Anti-apoptotic MCL-1 localizes to the mitochondrial matrix and couples mitochondrial fusion to respiration
MCL-1 is an anti-apoptotic BCL-2 family member and is frequently upregulated in cancer, but the mechanism by which it promotes cell survival has been elusive. Opferman and colleagues provide insight into this process by showing that MCL-1 exists in different forms with discrete localizations and functions. MCL-1 variants targeted to the outer mitochondrial membrane antagonize BAX and BAK activation, whereas an N-terminally truncated isoform localizes to the mitochondrial matrix and regulates mitochondrial metabolism.
- Rhonda M. Perciavalle
- , Daniel P. Stewart
- & Joseph T. Opferman
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Letter |
CDK5 and MEKK1 mediate pro-apoptotic signalling following endoplasmic reticulum stress in an autosomal dominant retinitis pigmentosa model
ER stress activates the unfolded protein response (UPR), which can ultimately result in apoptosis. Using a Drosophila model of ER stress, Ryoo and colleagues find that apoptosis is induced independently of the known UPR branches. They show that ER stress induces CDK5-mediated phosphorylation of MEKK1, which activates JNK and induces apoptosis.
- Min-Ji Kang
- , Jaehoon Chung
- & Hyung Don Ryoo
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Letter |
Toll-like receptor activation suppresses ER stress factor CHOP and translation inhibition through activation of eIF2B
Endoplasmic reticulum (ER) stress and activation of the unfolded protein response inhibits de novo protein translation and activates CHOP. However, the long-term induction of these pathways in response to prolonged ER stress would be detrimental. Tabas and colleagues now reveal a mechanism through which Toll-like receptor signalling suppresses CHOP activation and promotes protein translation, thus allowing cells to adapt to persistent ER stress.
- Connie W. Woo
- , Lydia Kutzler
- & Ira Tabas
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Letter |
Caspase 8 inhibits programmed necrosis by processing CYLD
Caspase 8 is known to suppress necroptosis, but its relevant target protein was unknown. Ting and colleagues show that caspase 8 cleaves the deubiquitylase CYLD to inhibit necroptosis and promote cell survival.
- Marie Anne O’Donnell
- , Eva Perez-Jimenez
- & Adrian T. Ting
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Article |
Autophagy machinery mediates macroendocytic processing and entotic cell death by targeting single membranes
An epithelial cell can be engulfed by its neighbour through entosis, which frequently results in the death of the entosed cell. Overholtzer and colleagues show that the autophagy machinery is recruited to single-membrane entotic vacuoles and promotes their fusion with lysosomes. Single-membrane macrophage phagosomes containing apoptotic cells are also targeted for destruction by the autophagy pathway.
- Oliver Florey
- , Sung Eun Kim
- & Michael Overholtzer
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Article |
Bcl-xL regulates metabolic efficiency of neurons through interaction with the mitochondrial F1FO ATP synthase
ATP production by mitochondria requires the efficient flow of protons through the F1FO ATP-synthase complex. Jonas and colleagues show that Bcl-xL interacts with the F1FO complex in the mitochondrial matrix and increases the efficiency of this enzyme by decreasing proton leak.
- Kambiz N. Alavian
- , Hongmei Li
- & Elizabeth A. Jonas
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Article |
Midbody accumulation through evasion of autophagy contributes to cellular reprogramming and tumorigenicity
Doxsey and colleagues report that midbodies accumulate in stem cells, including induced pluripotent stem cells and potential cancer-initiating cells. Loss of midbodies accompanies stem-cell differentiation and is mediated through binding of the autophagy receptor NBR1 to the midbody protein CEP55. Downregulation of NBR1 is associated with enrichment of midbodies, enhanced reprogramming and increased tumorigenicity in cancer cells.
- Tse-Chun Kuo
- , Chun-Ting Chen
- & Stephen Doxsey
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Article |
Cdk5-mediated phosphorylation of endophilin B1 is required for induced autophagy in models of Parkinson's disease
Cdk5-mediated phosphorylation of endophilin B1 is shown to be required for autophagy induction in starved neurons, by promoting endophilin B1 dimerization and recruitment of the autophagy regulator UVRAG. This effect leads to neuronal loss in models of Parkinson’s disease.
- Alan S. L. Wong
- , Rebecca H. K. Lee
- & Nancy Y. Ip
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Article |
During autophagy mitochondria elongate, are spared from degradation and sustain cell viability
Mitochondria are found to fuse at the onset of autophagy. This event, which is regulated by a cyclic AMP–PKA (protein kinase A) signalling pathway, increases ATP synthase activity to prevent starvation-induced cell death.
- Ligia C. Gomes
- , Giulietta Di Benedetto
- & Luca Scorrano
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News & Views |
Entosis: aneuploidy by invasion
Aneuploidy is one of the most prevalent phenotypes of human tumours, but the underlying cause of this phenomenon remains highly debated. Entosis, the invasion of a living cell into another cell's cytoplasm, is now shown to perturb cytokinesis and induce the formation of aneuploid cells.
- Aniek Janssen
- & René H. Medema
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News & Views |
Necrotic cell death: harnessing the Dark side of the Force in mammary gland involution
In response to major cellular insults, a massive increase in lysosomal membrane permeability (LMP) leads to necrosis. Data now reveal that this potent lysosomal-mediated necrotic cell-death machinery can also be harnessed for complex physiological processes, such as post-lactation mammary gland involution.
- Cliff J. Luke
- & Gary A. Silverman
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Review Article |
Integrating the mechanisms of apoptosis induced by endoplasmic reticulum stress
- Ira Tabas
- & David Ron
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Letter |
Stat3 controls lysosomal-mediated cell death in vivo
Post-lactational involution in the mammary gland is shown to be accomplished by a lysosome-mediated cell death pathway. This pathway is independent of the executioner caspases 3, 6 and 7, and instead relies on Stat3-mediated upregulation of cathepsins.
- Peter A. Kreuzaler
- , Anna D. Staniszewska
- & Christine J. Watson
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Letter |
Loss of the RhoGAP SRGP-1 promotes the clearance of dead and injured cells in Caenorhabditis elegans
Apoptotic cell corpses are engulfed and removed through an evolutionarily conserved pathway. In Caenorhabditis elegans, inhibition of the Rac GAP SRGP-1 permits sick or dying cells to escape clearance by this pathway.
- Lukas J. Neukomm
- , Andreas P. Frei
- & Michael O. Hengartner
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Article |
Human IRGM regulates autophagy and cell-autonomous immunity functions through mitochondria
IRGM is a human GTPase that triggers autophagy in response to pathogen infection. On Mycobacteria infection, IRGM binds the mitochondrial cardiolipin to induce mitochondrial fission and a general autophagy response. It can also trigger autophagy-independent mitochondria-mediated cell death.
- Sudha B. Singh
- , Wojciech Ornatowski
- & Vojo Deretic
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Editorial |
Focusing on Autophagy
Autophagy targets portions of cytoplasm, damaged organelles and proteins for lysosomal degradation and has crucial roles in development and disease. This issue presents a series of specially commissioned articles that highlight recent developments and emerging themes in this area.
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Perspective |
Selective autophagy: ubiquitin-mediated recognition and beyond
- Claudine Kraft
- , Matthias Peter
- & Kay Hofmann
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Review Article |
Autophagy in mammalian development and differentiation
- Noboru Mizushima
- & Beth Levine
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Article |
Cytoskeletal keratin glycosylation protects epithelial tissue from injury
Keratin 8 and 18 protect hepatocytes from apoptosis. Inhibiting keratin 18 glycosylation is shown to sensitize cells to liver and pancreatic injury and apoptosis, through a pathway involving Akt and PKCθ.
- Nam-On Ku
- , Diana M. Toivola
- & M. Bishr Omary
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Article |
Defective CFTR induces aggresome formation and lung inflammation in cystic fibrosis through ROS-mediated autophagy inhibition
Mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) lead to accumulation of proteins aggregates in airways. Mutated CFTR promotes transglutaminases-mediated crosslinking of beclin 1, a positive regulator of autophagy, to induce accumulation of LC3-binding protein p62 and prevent autophagic degradation of aggregates.
- Alessandro Luciani
- , Valeria Rachela Villella
- & Luigi Maiuri
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Article |
Plasma membrane contributes to the formation of pre-autophagosomal structures
Both endoplasmic reticulum and mitochondrial membranes are thought to contribute to the formation of autophagosomes during autophagy induction. We now learn that plasma membrane is also involved, and is partly targeted to the growing autophagosome through clathrin-mediated endocytosis.
- Brinda Ravikumar
- , Kevin Moreau
- & David C. Rubinsztein
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Article |
Autophagy negatively regulates Wnt signalling by promoting Dishevelled degradation
The significance of autophagy for signal transduction has been unclear. Autophagy negatively regulates Wnt signalling by promoting Dishevelled (Dvl) degradation. The von Hippel-Lindau protein ubiquitylates Dvl to faciliatate its recruitment to autophagosomes through p62.
- Chan Gao
- , Weipeng Cao
- & Ye-Guang Chen
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News & Views |
Tagging the dead: a bridging factor for Caenorhabditis elegans phagocyte receptors
Recognition of apoptotic cells by phagocytic cells in Caenorhabditis elegans has been something of a mystery. A secreted transthyretin-like protein, TTR-52, has been identified as a bridging molecule between apoptotic cells and CED-1 on the phagocytic cells that engulf them.
- Rachael Rutkowski
- & Anton Gartner
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Article |
Cytosolic FoxO1 is essential for the induction of autophagy and tumour suppressor activity
Autophagy is involved in tumour suppression. Cytoplasmic FoxO1 is acetylated in response to stress and binds the autophagy regulator Atg7 to promote autophagy, cell death and tumour suppression, independently of its transcriptional activity.
- Ying Zhao
- , Jing Yang
- & Wei-Guo Zhu
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Article |
Caenorhabditis elegans transthyretin-like protein TTR-52 mediates recognition of apoptotic cells by the CED-1 phagocyte receptor
Recognition of apoptotic cells by phagocytes is not fully understood. In C. elegans, the transthyretin-like protein, TTR-52, is secreted by the endoderm and clusters around apoptotic cells, inducing their engulfment through the CED-1/6/7 pathway.
- Xiaochen Wang
- , Weida Li
- & Ding Xue
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Article |
Bcl-2 and accelerated DNA repair mediates resistance of hair follicle bulge stem cells to DNA-damage-induced cell death
Hair follicle stem cells have increased resistance to DNA damage-induced cell death. This is due to higher expression of Bcl2 and to a faster non-homologous end-joining (NHEJ) DNA repair activity, which attenuates p53 activation.
- Panagiota A. Sotiropoulou
- , Aurélie Candi
- & Cédric Blanpain
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Article |
The role of Cdk5-mediated apurinic/apyrimidinic endonuclease 1 phosphorylation in neuronal death
Cyclin-dependent kinase 5 phosphorylates Ape1, a regulator of base excision repair, to reduce its endonuclease activity and increase neuronal death following treatment with neurotoxins. Interestingly, increase in Ape1 phosphorylation is also observed in patients with neurodegenerative diseases.
- En Huang
- , Dianbo Qu
- & David S. Park
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Article |
MTCH2/MIMP is a major facilitator of tBID recruitment to mitochondria
BH3-only protein tBID induces mitochondrial outer membrane permeabilization in response to death receptor activation. The mitochondrial carrier homologue 2 (MTCH2) protein acts as the tBID receptor on the mitochondria and is required for fas-induced cell death in mouse liver.
- Yehudit Zaltsman
- , Liat Shachnai
- & Atan Gross
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Turning Points |
Signalling lessons from death receptors: the importance of cleavage
- Vishva M. Dixit
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Article |
The selective autophagy substrate p62 activates the stress responsive transcription factor Nrf2 through inactivation of Keap1
Impaired turnover of the autophagy substrate p62 leads to liver injury. p62 inhibits the ubiquitin ligase Keap1, leading to stabilization of the transcription factor Nrf2. High levels of p62 in autophagy deficient animals leads to unusually high expression of Nrf2 targets genes and results in liver injury.
- Masaaki Komatsu
- , Hirofumi Kurokawa
- & Masayuki Yamamoto
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Article |
PINK1/Parkin-mediated mitophagy is dependent on VDAC1 and p62/SQSTM1
The E3 ubiquitin ligase Parkin mediates the clearance of depolarized mitochondria through the autophagy pathway. PINK1 kinase activity is required for Parkin translocation to depolarized mitochondria where Parkin generates polyubiquitin chains on the voltage-dependent anion channel (VDAC1) to recruit the autophagic adaptor p62/SQSTM1.
- Sven Geisler
- , Kira M. Holmström
- & Wolfdieter Springer
Can autophagy promote longevity?
The origin of the autophagosomal membrane
Eaten alive: a history of macroautophagy