- Nucleophagy plays a major role in human diseases. [Journal Article]
- CDCurr Drug Targets 2018 May 17
- Nucleophagy is a selective autophagy, which selectively remove damaged or non-essential nuclear material from a cell by the autophagy pathway. Additionally, nucleophagy is crucial for promoting cell ...
Nucleophagy is a selective autophagy, which selectively remove damaged or non-essential nuclear material from a cell by the autophagy pathway. Additionally, nucleophagy is crucial for promoting cell longevity and ensure body proper function. Increasing evidences have shown that nucleophagy may play a major role in such human diseases as degenerative disorders, tumorigenesis, malnutrition and metabolic disorders, parakeratosis and psoriasis. Studies indicated that nucleophagy can improve degenerative disorders by delaying premature cell senescence, prevent malnutrition and metabolic disorder via maintaining nuclear structure and releasing nutrients for energy production, and alleviate parakeratosis and psoriasis. But the activation of nucleophagy appears to be a double-edged sword. Some studies indicated that overexpression of lamin B1 delays cell senescence. During the process of nucleophagy, appropriate nucleophagy can drive RAS-induced cell senescence and DNA damage-induced cell senescence so as to restrain cell proliferation. Besides, appropriate nucleophagy can degrade excessive amount of DNA content in polyploid tumor cells. Hence, selective nucleophagy may effectively protect cells from tumorigenesis and maintain cell and tissue integrity. However, excessive nucleophagy can attack normal cells and lead to an unforeseen cytotoxicity. In this paper, some signal pathways of nucleophagy occurrence were explained and the role of nucleophagy in these human diseases was analyzed. Our review indicates that nucleophagy may be a potential target in human diseases.
- A Review of Induction with Rabbit Antithymocyte Globulin in Pediatric Heart Transplant Recipients. [Journal Article]
- ATAnn Transplant 2018 May 15; 23:322-333
- Pediatric heart transplantation (pHTx) represents only a small proportion of cardiac transplants. Due to these low numbers, clinical data relating to induction therapy in this special population are ...
Pediatric heart transplantation (pHTx) represents only a small proportion of cardiac transplants. Due to these low numbers, clinical data relating to induction therapy in this special population are far less extensive than for adults. Induction is used more widely in pHTx than in adults, mainly because of early steroid withdrawal or complete steroid avoidance. Antithymocyte globulin (ATG) is the most frequent choice for induction in pHTx, and rabbit antithymocyte globulin (rATG, Thymoglobulin®) (Sanofi Genzyme) is the most widely-used ATG preparation. In the absence of large, prospective, blinded trials, we aimed to review the current literature and databases for evidence regarding the use, complications, and dosages of rATG. Analyses from registry databases suggest that, overall, ATG preparations are associated with improved graft survival compared to interleukin-2 receptor antagonists. Advantages for the use of rATG have been shown in low-risk patients given tacrolimus and mycophenolate mofetil in a steroid-free regimen, in sensitized patients with pre-formed alloantibodies and/or a positive donor-specific crossmatch, and in ABO-incompatible pHTx. Registry and clinical data have indicated no increased risk of infection or post-transplant lymphoproliferative disorder in children given rATG after pHTx. A total rATG dose in the range 3.5-7.5 mg/kg is advisable.
- C9ORF72 dipeptide repeat poly-GA inclusions promote: intracellular aggregation of phosphorylated TDP-43. [Journal Article]
- HMHum Mol Genet 2018 May 10
- Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are neurodegenerative diseases characterized by accumulation of insoluble aggregates of phosphorylated 43-kDa TAR DNA-binding prote...
Amyotrophic lateral sclerosis and frontotemporal lobar degeneration are neurodegenerative diseases characterized by accumulation of insoluble aggregates of phosphorylated 43-kDa TAR DNA-binding protein (TDP-43), and linked with abnormal expansion of a hexanucleotide repeat in an intron of chromosome 9 open reading frame 72 (C9ORF72). However, the relationship between C9ORF72 mutations and TDP-43 aggregation remains unknown. Non-ATG-dependent translation of C9ORF72 repeats produces dipeptide repeat (DPR) proteins, which form p62-positive aggregates in cerebral cortex and cerebellum of patients. Here, we show that the formation of poly-GA protein inclusions induced intracellular aggregation of endogenous and exogenous TDP-43 in cultured cells. Poly-GA aggregation preceded accumulation of phosphorylated TDP-43. These inclusions induced intracellular aggregation of phosphorylated TDP-43, but not tau or alpha-synuclein. Formation of phosphorylated TDP-43 aggregates depends on the number of poly-GA repeats. Detergent-insoluble fraction from cells co-expressing poly-GA and TDP-43 could function as seeds for further TDP-43 aggregation. These findings suggest a novel pathogenic mechanism that poly-GA protein aggregation directly promotes pathogenic changes of TDP-43 without formation of nuclear RNA foci containing GGGGCC repeat expansion or loss-of-function of the C9ORF72 protein.
- GSK3β‑mediated Ser156 phosphorylation modulates a BH3‑like domain in BCL2L12 during TMZ‑induced apoptosis and autophagy in glioma cells. [Journal Article]
- IJInt J Mol Med 2018 May 11
- BH3 domains, classified initially as BCL2 homology domains, participate in both apoptosis and autophagy. Beclin‑1 contains a BH3 domain, which is required for binding to antiapoptotic BCL2 homologs a...
BH3 domains, classified initially as BCL2 homology domains, participate in both apoptosis and autophagy. Beclin‑1 contains a BH3 domain, which is required for binding to antiapoptotic BCL2 homologs and BCL2‑mediated inhibition of autophagy. BCL2‑like 12 (BCL2L12) also harbors a BH3‑like domain, which is 12 residues long and contains a LXXXAE/D motif. In a yeast two‑hybrid system performed in the present study, BCL2L12 shared similar binding partnerships to antiapoptotic BCL2 homologs, such as Beclin‑1. In addition, this BH3‑like domain was involved in anti‑apoptosis and drug‑induced autophagy in glioma cell lines. Mutations in S156 and hydrophobic L213 to alanine counteracted the antiapoptotic properties of BCL2L12 and downregulated the activation of microtubule associated protein 1 light chain 3B (LC3B), autophagy‑related (ATG)12‑ATG5 conjugates and Beclin‑1, compared with a BCL2L12 wild‑type group. Molecular dynamics simulations revealed that phosphorylation at Ser156 of BCL2L12 (within α‑6 and α‑7 helices) influenced the BH3‑like domain conformation (α‑9 helix), indicating that glycogen synthase kinase (GSK) 3β‑mediated Ser156 phosphorylation modulated a BH3‑like domain in BCL2L12. Altogether, the present findings indicated that BCL2L12 may participate in anti‑apoptosis and autophagy via a BH3‑like domain and GSK3β‑mediated phosphorylation at Ser156. Furthermore, blockade of temozolomide (TMZ)‑induced autophagy by 3‑methyladenine (3‑MA) resulted in enhanced activation of apoptotic markers, as well as tumor suppresor protein p53 (p53) expression in U87MG cells. The present results suggested that p53 and O6‑methylguanine DNA methyltransferase activation, and BCL2, BCL‑extra large, Beclin‑1 and BCL2L12 expression may be used as a detection panel to determine which patients can benefit from TMZ and ABT‑737 combination treatment.
- Autophagy diminishes the early interferon-β response to influenza A virus resulting in differential expression of interferon-stimulated genes. [Journal Article]
- CDCell Death Dis 2018 May 10; 9(5):539
- Influenza A virus (IAV) infection perturbs metabolic pathways such as autophagy, a stress-induced catabolic pathway that crosstalks with cellular inflammatory responses. However, the impact of autoph...
Influenza A virus (IAV) infection perturbs metabolic pathways such as autophagy, a stress-induced catabolic pathway that crosstalks with cellular inflammatory responses. However, the impact of autophagy perturbation on IAV gene expression or host cell responses remains disputed. Discrepant results may be a reflection of in vivo studies using cell-specific autophagy-related (Atg) gene-deficient mouse strains, which do not delineate modification of developmental programmes from more proximal effects on inflammatory response. In vitro experiments can be confounded by gene expression divergence in wild-type cultivated cell lines, as compared to those experiencing long-term absence of autophagy. With the goal to investigate cellular processes within cells that are competent or incompetent for autophagy, we generated a novel experimental cell line in which autophagy can be restored by ATG5 protein stabilization in an otherwise Atg5-deficient background. We confirmed that IAV induced autophagosome formation and p62 accumulation in infected cells and demonstrated that perturbation of autophagy did not impact viral infection or replication in ATG5-stablized cells. Notably, the induction of interferon-stimulated genes (ISGs) by IAV was diminished when cells were autophagy competent. We further demonstrated that, in the absence of ATG5, IAV-induced interferon-β (IFN-β) expression was increased as compared to levels in autophagy-competent lines, a mechanism that was independent of IAV non-structural protein 1. In sum, we report that induction of autophagy by IAV infection reduces ISG expression in infected cells by limiting IFN-β expression, which may benefit viral replication and spread.
- Selective elimination of membrane-damaged chloroplasts via microautophagy. [Journal Article]
- PPPlant Physiol 2018 May 10
- Plant chloroplasts constantly accumulate damage caused by visible light during photosynthesis. Our previous study revealed that entire photodamaged chloroplasts are subjected to vacuolar digestion th...
Plant chloroplasts constantly accumulate damage caused by visible light during photosynthesis. Our previous study revealed that entire photodamaged chloroplasts are subjected to vacuolar digestion through an autophagy process termed chlorophagy; however, how this process is induced and executed remained poorly understood. In the current study, we monitored intracellular induction of chlorophagy in Arabidopsis leaves, and found that mesophyll cells damaged by high visible light (HL) displayed abnormal chloroplasts with a swollen shape and 2.5 times the volume of normal chloroplasts. In wild-type plants, the activation of chlorophagy decreased the number of swollen chloroplasts. In autophagy-deficient atg mutants, the swollen chloroplasts persisted, and dysfunctional chloroplasts that had lost chlorophyll fluorescence accumulated in the cytoplasm. Chloroplast swelling and subsequent induction of chlorophagy were suppressed by the application of exogenous mannitol to increase the osmotic pressure outside chloroplasts, or by overexpression of VIPP1, which maintains chloroplast envelope integrity. Microscopic observations of autophagy-related membranes showed that swollen chloroplasts were partly surrounded by autophagosomal structures, and were directly engulfed by the tonoplast, as in microautophagy. Our results indicate that an elevation in potential inside the chloroplast due to HL-derived envelope damage results in chloroplast swelling as an induction factor of chlorophagy, and that this process mobilizes entire chloroplasts via tonoplast-mediated sequestering to avoid the cytosolic accumulation of dysfunctional chloroplasts.
- Oxidative stress impairs autophagy through oxidation of ATG3 and ATG7. [Journal Article]
- AAutophagy 2018 May 10; :1-2
- Dysfunctional macroautophagy/autophagy has been causatively linked to aging and the pathogenesis of many diseases, which are also broadly characterized by dysregulated cellular redox. As the autophag...
Dysfunctional macroautophagy/autophagy has been causatively linked to aging and the pathogenesis of many diseases, which are also broadly characterized by dysregulated cellular redox. As the autophagy-related (ATG) conjugation systems that mediate autophagosome maturation are cysteine dependent, their oxidation may account for loss in this catabolic process under conditions of oxidative stress. During active autophagy, LC3 is transferred from the catalytic thiol of ATG7 to the active site thiol of ATG3, where it is conjugated to phosphatidylethanolamine. In our recent study, we show LC3 is bound to the catalytic thiols of inactive ATG3 and ATG7 through a stable thioester, which becomes transient upon autophagy stimulation. Transient interaction with LC3 exposes the catalytic thiols on ATG3 and ATG7, which under pro-oxidizing conditions undergo inhibitory oxidation. This process was found to be upregulated in aged mouse tissue and therefore may account, at least in part, for impaired autophagy observed during aging.
- Remission of type 1 diabetes mellitus recurrence 6 years after simultaneous pancreas and kidney transplantation. [Letter]
- AJAm J Transplant 2018 May 09
- Recurrence of type 1 diabetes mellitus (T1DM) is not frequent following pancreas transplantation and is generally considered to cause irreversible allograft failure despite rescue traitement1 .A 35-y...
Recurrence of type 1 diabetes mellitus (T1DM) is not frequent following pancreas transplantation and is generally considered to cause irreversible allograft failure despite rescue traitement1 .A 35-year-old woman experienced severe hyperglycaemia (>5 g/L) 6 years following a simultaneous pancreas and kidney (SPK) transplantation. Immunosuppressive treatment included induction with anti-thymocyte globuline (ATG) followed by a steroid-free regimen and a combination of tacrolimus and mycophenolate mofetil (MMF). This article is protected by copyright. All rights reserved.
- Low Autophagy (ATG) Gene Expression Is Associated with an Immature AML Blast Cell Phenotype and Can Be Restored during AML Differentiation Therapy. [Journal Article]
- OMOxid Med Cell Longev 2018; 2018:1482795
- Autophagy is an intracellular degradation system that ensures a dynamic recycling of a variety of building blocks required for self-renewal, homeostasis, and cell survival under stress. We used prima...
Autophagy is an intracellular degradation system that ensures a dynamic recycling of a variety of building blocks required for self-renewal, homeostasis, and cell survival under stress. We used primary acute myeloid leukemia (AML) samples and human AML cell lines to investigate the regulatory mechanisms of autophagy and its role in AML differentiation. We found a significantly lower expression of key autophagy- (ATG-) related genes in primary AML as compared to healthy granulocytes, an increased autophagic activity during all-trans retinoic acid- (ATRA-) induced neutrophil differentiation, and an impaired AML differentiation upon inhibition of ATG3, ATG4D, and ATG5. Supporting the notion of noncanonical autophagy, we found that ATRA-induced autophagy was Beclin1-independent compared to starvation- or arsenic trioxide- (ATO-) induced autophagy. Furthermore, we identified PU.1 as positive transcriptional regulator of ATG3, ATG4D, and ATG5. Low PU.1 expression in AML may account for low ATG gene expression in this disease. Low expression of the autophagy initiator ULK1 in AML can partially be attributed to high expression of the ULK1-targeting microRNA-106a. Our data clearly suggest that granulocytic AML differentiation relies on noncanonical autophagy pathways and that restoring autophagic activity might be beneficial in differentiation therapies.
New Search Next
- [Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis subsequent to rabbit antithymocyte globulin administration and successfully treated with rituximab in a patient with aplastic anemia]. [Journal Article]
- RKRinsho Ketsueki 2018; 59(4):407-413
- Rabbit antithymocyte globulin (ATG) is an effective immunosuppressive therapy for patients with aplastic anemia (AA). However, Epstein-Barr virus-associated lymphoproliferative disorder (EBV-LPD) is ...
Rabbit antithymocyte globulin (ATG) is an effective immunosuppressive therapy for patients with aplastic anemia (AA). However, Epstein-Barr virus-associated lymphoproliferative disorder (EBV-LPD) is a rare but serious complication of the therapy. An 81-year-old man was diagnosed with severe AA on the occasion of melena. Because cyclosporine monotherapy did not improve his condition, rabbit ATG was additionally administered. Thirty-one days after the administration of rabbit ATG, the patient presented with fever and general malaise. His liver and renal function tests showed rapid decline, and the patient went into shock. Although atypical lymphocytes in the peripheral blood, hepatosplenomegaly, and lymphadenopathy were not detected, the peripheral blood EBV-DNA load and serum ferritin levels were high, and his bone marrow aspiration specimen revealed hemophagocytic findings, leading to a diagnosis of EBV-LPD. He was treated with rituximab and recovered immediately. A total of 480 days have passed since the patient was administered the rabbit ATG, and he remains in AA remission without EBV-LPD relapse. This case suggests that rituximab is an effective therapy for EBV-LPD manifesting as EBV-associated hemophagocytic lymphohistiocytosis and indicates that monitoring the EBV-DNA load contributes to the diagnosis.