Two ubiquitin-like conjugation systems that mediate membrane formation during autophagy

2013 ◽  
Vol 55 ◽  
pp. 39-50 ◽  
Author(s):  
Hitoshi Nakatogawa
Keyword(s):  
Light Chain ◽  
Membrane Dynamics ◽  
The Other ◽  
Aminobutyric Acid ◽  
Amino Group ◽  
Autophagosome Formation ◽  
Acid Receptor ◽  
Receptor Associated Protein ◽  
Atg Proteins ◽  
C Terminus

In autophagy, the autophagosome, a transient organelle specialized for the sequestration and lysosomal or vacuolar transport of cellular constituents, is formed via unique membrane dynamics. This process requires concerted actions of a distinctive set of proteins named Atg (autophagy-related). Atg proteins include two ubiquitin-like proteins, Atg12 and Atg8 [LC3 (light-chain 3) and GABARAP (γ-aminobutyric acid receptor-associated protein) in mammals]. Sequential reactions by the E1 enzyme Atg7 and the E2 enzyme Atg10 conjugate Atg12 to the lysine residue in Atg5, and the resulting Atg12–Atg5 conjugate forms a complex with Atg16. On the other hand, Atg8 is first processed at the C-terminus by Atg4, which is related to ubiquitin-processing/deconjugating enzymes. Atg8 is then activated by Atg7 (shared with Atg12) and, via the E2 enzyme Atg3, finally conjugated to the amino group of the lipid PE (phosphatidylethanolamine). The Atg12–Atg5–Atg16 complex acts as an E3 enzyme for the conjugation reaction of Atg8; it enhances the E2 activity of Atg3 and specifies the site of Atg8–PE production to be autophagy-related membranes. Atg8–PE is suggested to be involved in autophagosome formation at multiple steps, including membrane expansion and closure. Moreover, Atg4 cleaves Atg8–PE to liberate Atg8 from membranes for reuse, and this reaction can also regulate autophagosome formation. Thus these two ubiquitin-like systems are intimately involved in driving the biogenesis of the autophagosomal membrane.

scholarly journals Development of new tools to study lipidated mammalian ATG8

2021 ◽  
Author(s):  
Sang-Won Park ◽  
Pureum Jeon ◽  
Akinori Yamasaki ◽  
Hye Eun Lee ◽  
Ji Young Mun ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Light Chain ◽  
Functional Significance ◽  
Aminobutyric Acid ◽  
Acid Receptor ◽  
Receptor Associated Protein ◽  
Selective Autophagy ◽  
Selective Interaction ◽  
Available Information ◽  
Lateral Sclerosis

Abstract Mammals conserve multiple mammalian ATG8 proteins (mATG8s) consisting of γ-aminobutyric acid receptor-associated protein (GABARAP) and microtubule-associated protein 1 light-chain 3 (LC3) subfamilies that tightly bind to the autophagic membranes in a lipidated form. They are crucial in selective autophagy and recruit proteins bearing LC3-interacting region (LIR) motifs. However, because limited research tools are available, information about the specific roles of each lipidated mATG8 in selective autophagy is scarce. Here, we identified LIR motifs specific to the lipidated form of each mATG8 and characterized the residues critical for their selective interaction using cell-based assays and structural analyses. Then, we used these selective LIR motifs to develop probes and irreversible deconjugases that targeted selective lipidated mATG8s in the autophagic membrane, revealing that lipidated GABARAP subfamily proteins regulate aggrephagy of amyotrophic lateral sclerosis-linked protein aggregates. Our tools will be useful in elucidating the functional significance of each mATG8 protein in autophagy research.

scholarly journals Structural catalog of core Atg proteins opens new era of autophagy research

2021 ◽  
Author(s):  
Kazuaki Matoba ◽  
Nobuo N Noda
Keyword(s):  
De Novo ◽  
Structural Information ◽  
Membrane Dynamics ◽  
Autophagosome Formation ◽  
New Era ◽  
Intracellular Degradation ◽  
Atg Proteins ◽  
Biological Studies ◽  
Evolutionarily Conserved ◽  
Biological Methods

Summary Autophagy, which is an evolutionarily conserved intracellular degradation system, involves de novo generation of autophagosomes that sequester and deliver diverse cytoplasmic materials to the lysosome for degradation. Autophagosome formation is mediated by approximately 20 core autophagy-related (Atg) proteins, which collaborate to mediate complicated membrane dynamics during autophagy. To elucidate the molecular functions of these Atg proteins in autophagosome formation, many researchers have tried to determine the structures of Atg proteins by using various structural biological methods. Although not sufficient, the basic structural catalog of all core Atg proteins was established. In this review article, we summarize structural biological studies of core Atg proteins, with an emphasis on recently unveiled structures, and describe the mechanistic breakthroughs in autophagy research that have derived from new structural information.

THE METABOLISM OF PUTRESCINE (1,4-DIAMINOBUTANE) BY MYCOBACTERIA ISOLATED FROM FISH: II. STUDIES WITH ARSENITE-INHIBITED CELLS AND CELL-FREE EXTRACTS

1967 ◽  
Vol 13 (5) ◽  
pp. 521-531 ◽  
Author(s):  
T. P. T. Evelyn
Keyword(s):  
Succinic Acid ◽  
Tricarboxylic Acid Cycle ◽  
Significant Proportion ◽  
Tricarboxylic Acid ◽  
The Other ◽  
Aminobutyric Acid ◽  
Succinic Semialdehyde ◽  
Amino Group ◽  
Intact Cells ◽  
Acid Cycle

Three mycobacterial strains isolated from fish degraded putrescine by a pathway in which γ-aminobutyraldehyde (Δ′-pyrroline), γ-aminobutyric acid, succinic semialdehyde, and succinic acid were intermediates. These results agree substantially with those of other workers using different microorganisms. Intact cells utilized γ-aminobutyric acid in a transaminase reaction with endogenously supplied α-ketoglutarate to produce succinic semialdehyde and glutamate. Studies with arsenite-poisoned cells showed that a significant proportion of putrescine was metabolized via pyruvate and alanine. When putrescine-1,4-14C was substrate, HCl extracts of cells contained radioactive aspartate and glutamate in addition to alanine. The further metabolism of succinate therefore proceeded in two directions: one yielding oxalacetate and α-ketoglutarate by way of the tricarboxylic acid cycle, and the other branching off the cycle to yield pyruvate. Studies with cell-free extracts suggested that putrescine nitrogen was assimilated via glutamate, which served as the amino-group donor to yield alanine and aspartate.

scholarly journals Antagonistic effect of flumazenil on tiletamine-zolazepam-induced anaesthesia in Beagle dogs

2018 ◽  
Vol 63 (No. 12) ◽  
pp. 555-560
Author(s):  
J.Y. Lee ◽  
S.J. Son ◽  
S. Jang ◽  
S. Choi ◽  
D.W. Cho
Keyword(s):  
Adverse Effects ◽  
Saline Solution ◽  
Competitive Inhibition ◽  
Antagonistic Effect ◽  
The Other ◽  
Aminobutyric Acid ◽  
Beagle Dogs ◽  
Acid Receptor ◽  
Sedative Effects ◽  
Recovery Times

Benzodiazepines exert hypnotic/sedative effects through their inhibitory actions on the γ-aminobutyric acid receptor type A. Since flumazenil antagonises these effects through competitive inhibition of the receptor, it has been used to reverse the effect of benzodiazepines. The goal of this study was to characterise the antagonistic effect of flumazenil on anaesthesia induced by tiletamine-zolazepam in dogs. Nine healthy Beagle dogs (four males, five females) were used in this study. The dogs were administered 20 mg/kg of tiletamine-zolazepam intravenously and were then intravenously treated with saline solution (2 ml; control) or flumazenil twenty minutes after tiletamine-zolazepam administration at doses of 0.02, 0.04, 0.06, 0.08 or 0.16 mg/kg. Recovery times after the anaesthesia and cardiorespiratory variation were recorded for each dog. The results of this study indicate that the duration of reversal produced by doses of 0.04 and 0.06 mg/kg flumazenil was more effective than that produced by any of the other doses. In addition, sedation was rapidly reversible at 0.04 and 0.06 mg/kg without resedation. However, at doses of 0.08 and 0.16 mg/kg adverse effects such as shivering, rigidity and opisthotonos were observed. Thus, treatment with flumazenil at doses of 0.04 and 0.06 mg/kg could successfully reverse the anaesthetic effects induced by tiletamine-zolazepam.

scholarly journals Borna Disease Virus P Protein Affects Neural Transmission through Interactions with Gamma-Aminobutyric Acid Receptor-Associated Protein

2008 ◽  
Vol 82 (24) ◽  
pp. 12487-12497 ◽  
Author(s):  
Guiqing Peng ◽  
Yan Yan ◽  
Chengliang Zhu ◽  
Shiqun Wang ◽  
Xiaohong Yan ◽  
...  
Keyword(s):  
Disease Virus ◽  
Aminobutyric Acid ◽  
Gamma Aminobutyric Acid ◽  
Borna Disease Virus ◽  
Acid Receptor ◽  
Receptor Associated Protein ◽  
P Gene ◽  
P Protein ◽  
Neural Transmission ◽  
Borna Disease

ABSTRACT Borna disease virus (BDV) is one of the infectious agents that causes diseases of the central nervous system in a wide range of vertebrate species and, perhaps, in humans. The phosphoprotein (P) of BDV, an essential cofactor of virus RNA-dependent RNA polymerase, is required for virus replication. In this study, we identified the gamma-aminobutyric acid receptor-associated protein (GABARAP) with functions in neurobiology as one of the viral P protein-interacting cellular factors by using an approach of phage display-based protein-protein interaction analysis. Direct binding between GABARAP and P protein was confirmed by coimmunoprecipitation, protein pull-down, and mammalian two-hybrid analyses. GABARAP originally was identified as a linker between the gamma-aminobutyric acid receptor (GABAR) and the microtubule to regulate receptor trafficking and plays important roles in the regulation of the inhibitory neural transmitter gamma-aminobutyric acid (GABA). We showed that GABARAP colocalizes with P protein in the cells infected with BDV or transfected with the P gene, which resulted in shifting the localization of GABARAP from the cytosol to the nucleus. We further demonstrated that P protein blocks the trafficking of GABAR, a principal GABA-gated ion channel that plays important roles in neural transmission, to the surface of cells infected with BDV or transfected with the P gene. We proposed that during BDV infection, P protein binds to GABARAP, shifts the distribution of GABARAP from the cytoplasm to the nucleus, and disrupts the trafficking of GABARs to the cell membranes, which may result in the inhibition of GABA-induced currents and in the enhancement of hyperactivity and anxiety.

scholarly journals The X-ray Crystal Structure and Putative Ligand-derived Peptide Binding Properties of γ-Aminobutyric Acid Receptor Type A Receptor-associated Protein

2001 ◽  
Vol 277 (7) ◽  
pp. 5556-5561 ◽  
Author(s):  
David Knight ◽  
Richard Harris ◽  
Mark S. B. McAlister ◽  
John P. Phelan ◽  
Stella Geddes ◽  
...  
Keyword(s):  
Crystal Structure ◽  
Peptide Binding ◽  
Type A ◽  
Aminobutyric Acid ◽  
Receptor Type ◽  
Binding Properties ◽  
Acid Receptor ◽  
X Ray ◽  
Receptor Associated Protein

scholarly journals Russell Body Typhlitis: A Case Report and Literature Review

2021 ◽  
pp. 106689692110082
Author(s):  
Sarah Al-Rawaf ◽  
Salem Alowami ◽  
Robert Riddell ◽  
Asghar Naqvi
Keyword(s):  
Case Report ◽  
Literature Review ◽  
Light Chain ◽  
Plasma Cells ◽  
Gastrointestinal Disease ◽  
English Literature ◽  
The Other ◽  
Tubulovillous Adenoma ◽  
Inflammatory Polyp ◽  
Intracytoplasmic Inclusions

Russell bodies are accumulation of immunoglobulin in plasma cells forming intracytoplasmic inclusions. Russell body colitis is rare with only 3 cases described in the English literature up to date. We report a 78-year-old male with cirrhosis showing prominent cecal infiltration of Russell body containing plasma cells. Plasma cells showed no nuclear atypia or mitoses, and no evidence of light chain restriction. In this article, we report a fourth case of Russell body colitis, that is unique in being localized to the cecum in contrast to the other 3, 1 of which was in an inflammatory polyp in the sigmoid colon, 1 in a rectal tubulovillous adenoma and 1 as part of diffuse gastrointestinal disease. This is therefore the first report of localized Russell body typhlitis, occurring in a cirrhotic patient in whom an adjacent erosion was likely nonsteroidal anti-inflammatory drug-associated, a combination that may have facilitated the formation of Russell bodies.

Deficiency of the β3 subunit of the type A γ–aminobutyric acid receptor causes cleft palate in mice

1995 ◽  
Vol 11 (3) ◽  
pp. 344-346 ◽  
Author(s):  
Cymbeline T. Culiat ◽  
Lisa J. Stubbs ◽  
Richard P. Woychik ◽  
Liane B. Russell ◽  
Dabney K. Johnson ◽  
...  
Keyword(s):  
Cleft Palate ◽  
Type A ◽  
Aminobutyric Acid ◽  
Acid Receptor
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