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Jia Liu, Weijin Liu, Yongquan Lu, Hao Tian, Chunli Duan, Lingling Lu, Ge Gao, Xia Wu, Xiaomin Wang, Hui Yang
Parkinson disease (PD) is the second most common neurodegenerative disorder after Alzheimer disease and is caused by genetics, environmental factors and aging, with few treatments currently available. Apoptosis and macroautophagy/autophagy play critical roles in PD pathogenesis; as such, modulating their balance is a potential treatment strategy. BCL2 (B cell leukemia/lymphoma 2) is a key molecule regulating this balance. Piperlongumine (PLG) is an alkaloid extracted from Piper longum L. that has anti-inflammatory and anticancer effects...
February 13, 2018: Autophagy
Faxiang Li, Daichao Xu, Yingli Wang, Zixuan Zhou, Jianping Liu, Shichen Hu, Yukang Gong, Junying Yuan, Lifeng Pan
OPTN (optineurin), a ubiquitin-binding scaffold protein, functions as an important macroautophagy/autophagy receptor in selective autophagy processes. Mutations in OPTN have been linked with human neurodegenerative diseases including ALS and glaucoma. However, the mechanistic basis underlying the recognition of ubiquitin by OPTN and its regulation by TBK1-mediated phosphorylation are still elusive. Here, we demonstrate that the UBAN domain of OPTN preferentially recognizes linear ubiquitin chain and forms an asymmetric 2:1 stoichiometry complex with the linear diubiquitin...
February 2, 2018: Autophagy
Trent D Evans, Se-Jin Jeong, Xiangyu Zhang, Babak Razani
In the atherosclerotic plaque, macrophages are the key catabolic workhorse responsible for clearing lipid and dead cell debris. To survive the highly proinflammatory and lipotoxic plaque environment, macrophages must adopt strategies for maintaining tight homeostasis and self-renewal. Macroautophagy/autophagy is a pro-survival cellular pathway wherein damaged or excess cellular cargoes are encapsulated by a double-membrane compartment and delivered to the lysosome for hydrolysis. Previously, macrophage-specific autophagy deficiency has been shown to be atherogenic through several complementary mechanisms including hyperactivation of the inflammasome, defective efferocytosis, accumulation of cytotoxic protein aggregates, and impaired lipid degradation...
February 2, 2018: Autophagy
Magda Cannata Serio, Maria A Rujano, Matias Simons
The biogenesis of the proton pump V-ATPase commences with the assembly of the proton pore sector V0 in the endoplasmic reticulum (ER). This process occurs under the control of a group of assembly factors whose mutations have recently been shown to cause glycosylation disorders with overlapping phenotypes in humans. Using whole exome sequencing, we demonstrate that mutations of the accessory V-ATPase subunit ATP6AP2 cause a similar disease characterized by hepatosteatosis, lipid abnormalities, immunodeficiency and cognitive impairment...
February 1, 2018: Autophagy
Shai Bel, Lora V Hooper
Secretion of antimicrobial proteins is an important host defense mechanism against bacteria, yet how secretory cells maintain function during bacterial invasion has been unclear. We discovered that Paneth cells, specialized secretory cells in the small intestine, react to bacterial invasion by rerouting a critical secreted antibacterial protein through a macroautophagy/autophagy-based secretion system termed secretory autophagy. Mice harboring a mutation in an essential autophagy gene, a mutation which is common in Crohn disease patients, cannot reroute their antimicrobial cargo during bacterial invasion and thus have compromised innate immunity...
February 1, 2018: Autophagy
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February 1, 2018: Autophagy
Olga Baron, Manolis Fanto
Macroautophagy/autophagy influences onset and progression of several human neurodegenerative diseases, because of its critical role as a regulator of neuronal proteostasis and organelle quality control. In many neurodegenerative diseases, impairment in autophagy is thought to play a fundamental part in the terminal phases of cellular degeneration and death. However, the ultimate mechanism of neuronal cell death remains elusive. In a recent study we have identified a new form of regulated cell death, which arises upon autophagy inhibition...
February 1, 2018: Autophagy
Ying Song, Dantong Shang, Hanhua Cheng, Rongjia Zhou
Macroautophagy/autophagy is a catabolic process that is essential for cellular homeostasis. How autophagosomal vesicle forms in a spatio-temporally regulated manner remains elusive. Our recent study revealed that small GTPase, RAB37 (RAB37, member RAS oncogene family), functions as a key organizer of autophagosomal membrane biogenesis. RAB37 interacts with ATG5 (autophagy related 5) and promotes autophagosome formation by modulating ATG12-ATG5-ATG16L1 complex assembly. These findings provide new insights into autophagy regulation...
February 1, 2018: Autophagy
Vicente Valenzuela, Melissa Nassif, Claudio Hetz
In recent years, the role of autophagy in the pathogenesis of most neurodegenerative diseases has transited into a limbo of protective or detrimental effects. Genetic evidence indicates that mutations in autophagy-regulatory genes can result in the occurrence of amyotrophic lateral sclerosis (ALS), suggesting a physiological role of the pathway to motoneuron function. However, experimental manipulation of autophagy in ALS models led to conflicting results depending on the intervention strategy and the disease model used...
February 1, 2018: Autophagy
Lun Zhao, Li Deng, Qing Zhang, Xue Jing, Meng Ma, Bin Yi, Jing Wen, Chaozhi Ma, Jinxing Tu, Tingdong Fu, Jinxiong Shen
Sulfonylurea (SU) herbicides inhibit branched-chain amino acid (BCAA) biosynthesis by targeting acetolactate synthase. Plants have evolved target-site resistance and metabolic tolerance to SU herbicides; the GCN2 (general control non-repressible 2) pathway is also involved in SU tolerance. Here, we report a novel SU tolerance mechanism, autophagy, which we call 'homeostatic tolerance,' is involved in amino acid signaling in Arabidopsis. The activation and reversion of autophagy and GCN2 by the SU herbicide tribenuron-methyl (TM) and exogenous BCAA, respectively, confirmed that TM-induced BCAA starvation is responsible for the activation of autophagy and GCN2...
January 29, 2018: Autophagy
Barry Jutten, Tom G Keulers, Hanneke J M Peeters, Marco B E Schaaf, Kim G M Savelkouls, Inge Compter, Ruud Clarijs, Olaf E M G Schijns, Linda Ackermans, Onno P M Teernstra, Marijke I Zonneveld, Resi M E Colaris, Ludwig Dubois, Marc A Vooijs, Johan Bussink, Julio Sotelo, Jan Theys, Guido Lammering, Kasper M A Rouschop
Expression of EGFRvIII is frequently observed in glioblastoma and is associated with increased cellular proliferation, enhanced tolerance to metabolic stresses, accelerated tumor growth, therapy resistance and poor prognosis. We observed that expression of EGFRvIII elevates the activation of macroautophagy/autophagy during starvation and hypoxia and explored the underlying mechanism and consequence. Autophagy was inhibited (genetically or pharmacologically) and its consequence for tolerance to metabolic stress and its therapeutic potential in (EGFRvIII+) glioblastoma was assessed in cellular systems, (patient derived) tumor xenopgrafts and glioblastoma patients...
January 29, 2018: Autophagy
Andreas Struchtrup, Antonia Wiegering, Björn Stork, Ulrich Rüther, Christoph Gerhardt
Previously, macroautophagy/autophagy was demonstrated to be regulated inter alia by the primary cilium. Mutations in RPGRIP1L cause ciliary dysfunctions resulting in severe human diseases summarized as ciliopathies. Recently, we showed that RPGRIP1L deficiency leads to a decreased proteasomal activity at the ciliary base in mice. Importantly, the drug-induced restoration of proteasomal activity does not rescue ciliary length alterations in the absence of RPGRIP1L indicating that RPGRIP1L affects ciliary function also via other mechanisms...
January 26, 2018: Autophagy
Fu-Xin Wang, Yuan-Ming Luo, Zi-Qin Ye, Xue Cao, Jing-Nan Liang, Qian Wang, Yao Wu, Jia-He Wu, Hai-Yun Wang, Min Zhang, Huan-Qing Cheng, Gui-Xian Xia
The mechanisms underlying the functional link between autophagy and plant innate immunity remain largely unknown. In this study, we investigated the autophagy-mediated plant defense responses against Verticillium dahliae (V. dahliae) infection by comparative proteomics and cellular analyses. An assessment of the autophagy activity and disease development showed that autophagic processes were tightly related to the tolerance of Arabidopsis plant to Verticillium wilt. An isobaric tags for relative and absolute quantification (iTRAQ)-based proteomics analysis was performed, and we identified a total of 780 differentially accumulated proteins (DAPs) between wild-type and mutant atg10-1 Arabidopsis plants upon V...
January 25, 2018: Autophagy
Patricia García-Sanz, Lorena Orgaz, José M Fuentes, Carlos Vicario, Rosario Moratalla
Lipid and cholesterol metabolism might play a role in the pathogenesis of Parkinson disease (PD). However, the association between cholesterol and PD is not clearly established. Cholesterol accumulation is closely related to the expression of multilamellar bodies (MLBs). Also, cholesterol controls autophagosome transport. Thus, impaired cholesterol and autophagosome trafficking might lead to robust autophagic vacuole accumulation. Our recent work provides the first evidence that the presence of the N370S GBA/GBA1 mutation produces an accumulation of cholesterol, which alters autophagy-lysosome function with the appearance of MLBs, rendering the cell more vulnerable and sensitive to apoptosis...
January 25, 2018: Autophagy
Christian W Keller, Jan D Lünemann
Reactivation and expansion of myelin-reactive CD4+ T cells within the central nervous system (CNS) are considered to play a key role in the pathogenesis of multiple sclerosis (MS) and its animal model, experimental autoimmune encephalomyelitis (EAE). We demonstrated that accumulation of myelin-specific CD4+ T cells within the CNS and subsequent clinical disease development require autophagy related (ATG) protein-dependent phagocytosis in dendritic cells (DCs). Genetic ablation of this pathway impairs presentation of myelin-associated antigen following phagocytosis of injured, phosphatidylserine-exposing oligodendroglial cells...
January 25, 2018: Autophagy
Min Zhang, Yu Wang, Liang Ge
Autophagosomal membrane sources generate autophagic membrane precursors, which later assemble into the double-membrane autophagosome. The key events happening on the membrane sources during autophagic membrane generation remain poorly characterized. Our previous work found the ER-Golgi intermediate compartment (ERGIC) as a membrane source for the phagophore, the precursor to the autophagosome. A relocation of the COPII machinery from the ER-exit sites (ERES) to the ERGIC generates vesicles for LC3 lipidation...
January 25, 2018: Autophagy
Margie N Sutton, Hailing Yang, Gilbert Y Huang, Caroline Fu, Michael Pontikos, Yan Wang, Weiqun Mao, Lan Pang, Maojie Yang, Jinsong Liu, Jan Parker-Thornburg, Zhen Lu, Robert C Bast
Among the 3 GTPases in the DIRAS family, DIRAS3/ARHI is the best characterized. DIRAS3 is an imprinted tumor suppressor gene that encodes a 26-kDa GTPase that shares 60% homology to RAS and RAP. DIRAS3 is downregulated in many tumor types, including ovarian cancer, where re-expression inhibits cancer cell growth, reduces motility, promotes tumor dormancy and induces macroautophagy/autophagy. Previously, we demonstrated that DIRAS3 is required for autophagy in human cells. Diras3 has been lost from the mouse genome during evolutionary re-arrangement, but murine cells can still undergo autophagy...
January 25, 2018: Autophagy
Muhammad Zaeem Noman, Guy Berchem, Bassam Janji
Solid tumors are able to establish and sustain an immune suppressive microenvironment, which prevents the infiltration of cytotoxic effector immune cells into the tumor bed. We showed that genetic targeting of the macroautophagy/autophagy gene Becn1/Beclin1 in B16-F10 tumors inhibits their growth by inducing a massive infiltration of functional natural killer (NK) cells into the tumor bed. Such infiltration is primarily due to the ability of BECN1-defective tumor cells to overexpress and release CCL5 cytokine in the tumor microenvironment by a mechanism involving the activation of the MAPK8/JNK-JUN/c-Jun signaling pathway...
January 25, 2018: Autophagy
Santiago Lima, Kazuaki Takabe, Jason Newton, Kumar Saurabh, Megan M Young, Andreia Machado Leopoldino, Nitai C Hait, Jane L Roberts, Hong-Gang Wang, Paul Dent, Sheldon Milstien, Laurence Booth, Sarah Spiegel
The bioactive sphingolipid metabolite sphingosine-1-phosphate (S1P) and the enzyme that produces it, SPHK1 (sphingosine kinase 1), regulate many processes important for the etiology of cancer. It has been suggested that SPHK1 levels are regulated by the tumor suppressor protein TP53, a key regulator of cell cycle arrest, apoptosis, and macroautophagy/autophagy. However, little is still known of the relationship between TP53 and SPHK1 activity in the regulation of these processes. To explore this link, we examined the effects of inhibiting SPHK1 in wild-type and TP53 null cancer cell lines...
January 25, 2018: Autophagy
Sandrine Silvente-Poirot, Gregory Ségala, Mathias C Poirot, Marc Poirot
Dendrogenin A (DDA) is a mammalian metabolite that displays anticancer and chemopreventive properties in mice. At the cancer cell level, DDA induces differentiation and death. We investigated herein the nature of DDA cytoxicity in cancer cells. We showed that DDA triggers biochemical and cellular features of macroautophagy/autophagy and that autophagy is cytotoxic. DDA induces both the accumulation of pro-lysosomal sterols and stimulates the expression of regulators of autophagy such as NR4A, LC3 and TFEB through binding to the liver X receptor (LXR), a ligand-dependent transcription factor consisting of 2 isoforms, NR1H2 and NR1H3...
January 25, 2018: Autophagy
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