Targeting SQSTM1/p62 induces cargo loading failure and converts autophagy to apoptosis via NBK/Bik.

Abstract:

:In selective autophagy, the adaptor protein SQSTM1/p62 plays a critical role in recognizing/loading cargo (e.g., malfolded proteins) into autophagosomes for lysosomal degradation. Here we report that whereas SQSTM1/p62 levels fluctuated in a time-dependent manner during autophagy, inhibition or knockdown of Cdk9/cyclin T1 transcriptionally downregulated SQSTM1/p62 but did not affect autophagic flux. These interventions, or short hairpin RNA (shRNA) directly targeting SQSTM1/p62, resulted in cargo loading failure and inefficient autophagy, phenomena recently described for Huntington's disease neurons. These events led to the accumulation of the BH3-only protein NBK/Bik on endoplasmic reticulum (ER) membranes, most likely by blocking loading and autophagic degradation of NBK/Bik, culminating in apoptosis. Whereas NBK/Bik upregulation was further enhanced by disruption of distal autophagic events (e.g., autophagosome maturation) by chloroquine (CQ) or Lamp2 shRNA, it was substantially diminished by inhibition of autophagy initiation (e.g., genetically by shRNA targeting Ulk1, beclin-1, or Atg5 or pharmacologically by 3-methyladenine [3-MA] or spautin-1), arguing that NBK/Bik accumulation stems from inefficient autophagy. Finally, NBK/Bik knockdown markedly attenuated apoptosis in vitro and in vivo. Together, these findings identify novel cross talk between autophagy and apoptosis, wherein targeting SQSTM1/p62 converts cytoprotective autophagy to an inefficient form due to cargo loading failure, leading to NBK/Bik accumulation, which triggers apoptosis.

journal_name

Mol Cell Biol

authors

Chen S,Zhou L,Zhang Y,Leng Y,Pei XY,Lin H,Jones R,Orlowski RZ,Dai Y,Grant S

doi

10.1128/MCB.01383-13

subject

Has Abstract

pub_date

2014-09-15 00:00:00

pages

3435-49

issue

18

eissn

0270-7306

issn

1098-5549

pii

MCB.01383-13

journal_volume

34

pub_type

杂志文章
  • Occludin S471 Phosphorylation Contributes to Epithelial Monolayer Maturation.

    abstract::Multiple organ systems require epithelial barriers for normal function, and barrier loss is a hallmark of diseases ranging from inflammation to epithelial cancers. However, the molecular processes regulating epithelial barrier maturation are not fully elucidated. After contact, epithelial cells undergo size-reductive ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/MCB.00053-16

    authors: Bolinger MT,Ramshekar A,Waldschmidt HV,Larsen SD,Bewley MC,Flanagan JM,Antonetti DA

    更新日期:2016-07-14 00:00:00

  • A weak spliceosome-binding domain of Yju2 functions in the first step and bypasses Prp16 in the second step of splicing.

    abstract::Yju2 is an essential splicing factor required for the first catalytic step after the action of Prp2. We dissected the structure of Yju2 and found that the amino (Yju2-N) and carboxyl (Yju2-C) halves of the protein can be separated and reconstituted for Yju2 function both in vivo and in vitro. Yju2-N has a weak affinit...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/MCB.00035-13

    authors: Chiang TW,Cheng SC

    更新日期:2013-05-01 00:00:00

  • Effects of Wnt signaling on brown adipocyte differentiation and metabolism mediated by PGC-1alpha.

    abstract::Activation of canonical Wnt signaling inhibits brown adipogenesis of cultured cells by impeding induction of PPARgamma and C/EBPalpha. Although enforced expression of these adipogenic transcription factors restores lipid accumulation and expression of FABP4 in Wnt-expressing cells, additional expression of PGC-1alpha ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/MCB.25.4.1272-1282.2005

    authors: Kang S,Bajnok L,Longo KA,Petersen RK,Hansen JB,Kristiansen K,MacDougald OA

    更新日期:2005-02-01 00:00:00

  • Differential effects of Cdc68 on cell cycle-regulated promoters in Saccharomyces cerevisiae.

    abstract::Swi4 and Swi6 form a complex which is required for Start-dependent activation of HO and for high-level expression of G1 cyclin genes CLN1 and CLN2. To identify other regulators of this pathway, we screened for dominant, recessive, conditional, and allele-specific suppressors of swi4 mutants. We isolated 16 recessive s...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.14.11.7455

    authors: Lycan D,Mikesell G,Bunger M,Breeden L

    更新日期:1994-11-01 00:00:00

  • Id helix-loop-helix proteins antagonize pax transcription factor activity by inhibiting DNA binding.

    abstract::The Id subfamily of helix-loop-helix (HLH) proteins plays a fundamental role in the regulation of cellular proliferation and differentiation. The major mechanism by which Id proteins are thought to inhibit differentiation is through interaction with other HLH proteins and inhibition of their DNA-binding activity. Howe...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/MCB.21.2.524-533.2001

    authors: Roberts EC,Deed RW,Inoue T,Norton JD,Sharrocks AD

    更新日期:2001-01-01 00:00:00

  • Wing-to-Leg homeosis by spineless causes apoptosis regulated by Fish-lips, a novel leucine-rich repeat transmembrane protein.

    abstract::Growth, patterning, and apoptosis are mutually interactive during development. For example, cells that select an abnormal fate in a developing field are frequently removed by apoptosis. An important issue in this process that needs to be resolved is the mechanism used by cells to discern their correct fate from an abn...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/MCB.25.8.3140-3150.2005

    authors: Adachi-Yamada T,Harumoto T,Sakurai K,Ueda R,Saigo K,O'Connor MB,Nakato H

    更新日期:2005-04-01 00:00:00

  • Modulation of transforming growth factor type beta action by activated ras and c-myc.

    abstract::Transfection of C3H/10T1/2 cells with a c-myc gene resulted in the acquisition of responsiveness to transforming growth factor type beta. Cells transfected with an activated H-ras gene or an H-ras and c-myc gene, however, exhibited a transformed morphology and spontaneous soft-agar growth, a phenotype induced reversib...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.7.7.2649

    authors: Leof EB,Proper JA,Moses HL

    更新日期:1987-07-01 00:00:00

  • mRNA Processing Factor CstF-50 and Ubiquitin Escort Factor p97 Are BRCA1/BARD1 Cofactors Involved in Chromatin Remodeling during the DNA Damage Response.

    abstract::The cellular response to DNA damage is an intricate mechanism that involves the interplay among several pathways. In this study, we provide evidence of the roles of the polyadenylation factor cleavage stimulation factor 50 (CstF-50) and the ubiquitin (Ub) escort factor p97 as cofactors of BRCA1/BARD1 E3 Ub ligase, fac...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/MCB.00364-17

    authors: Fonseca D,Baquero J,Murphy MR,Aruggoda G,Varriano S,Sapienza C,Mashadova O,Rahman S,Kleiman FE

    更新日期:2018-01-29 00:00:00

  • Peroxisome proliferator-activated receptor gamma target gene encoding a novel angiopoietin-related protein associated with adipose differentiation.

    abstract::The nuclear receptor peroxisome proliferator-activated receptor gamma regulates adipose differentiation and systemic insulin signaling via ligand-dependent transcriptional activation of target genes. However, the identities of the biologically relevant target genes are largely unknown. Here we describe the isolation a...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.20.14.5343-5349.2000

    authors: Yoon JC,Chickering TW,Rosen ED,Dussault B,Qin Y,Soukas A,Friedman JM,Holmes WE,Spiegelman BM

    更新日期:2000-07-01 00:00:00

  • A functional screen for Myc-responsive genes reveals serine hydroxymethyltransferase, a major source of the one-carbon unit for cell metabolism.

    abstract::A cDNA library enriched with Myc-responsive cDNAs but depleted of myc cDNAs was used in a functional screen for growth enhancement in c-myc-null cells. A cDNA clone for mitochondrial serine hydroxymethyltransferase (mSHMT) that was capable of partial complementation of the growth defects of c-myc-null cells was identi...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.22.16.5793-5800.2002

    authors: Nikiforov MA,Chandriani S,O'Connell B,Petrenko O,Kotenko I,Beavis A,Sedivy JM,Cole MD

    更新日期:2002-08-01 00:00:00

  • TRAM2 protein interacts with endoplasmic reticulum Ca2+ pump Serca2b and is necessary for collagen type I synthesis.

    abstract::Cotranslational insertion of type I collagen chains into the lumen of the endoplasmic reticulum (ER) and their subsequent folding into a heterotrimeric helix is a complex process which requires coordinated action of the translation machinery, components of translocons, molecular chaperones, and modifying enzymes. Here...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.24.4.1758-1768.2004

    authors: Stefanovic B,Stefanovic L,Schnabl B,Bataller R,Brenner DA

    更新日期:2004-02-01 00:00:00

  • Exclusive homodimerization of the orphan receptor hepatocyte nuclear factor 4 defines a new subclass of nuclear receptors.

    abstract::Hepatocyte nuclear factor 4 (HNF-4), a highly conserved member of the steroid hormone receptor superfamily critical for development and liver-specific gene expression, is very similar to another superfamily member, retinoid X receptor alpha (RXR alpha), in overall amino acid sequence and DNA binding specificity. Since...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.15.9.5131

    authors: Jiang G,Nepomuceno L,Hopkins K,Sladek FM

    更新日期:1995-09-01 00:00:00

  • Endoplasmic reticulum stress accelerates p53 degradation by the cooperative actions of Hdm2 and glycogen synthase kinase 3beta.

    abstract::Inactivation of the tumor suppressor p53 by degradation is a mechanism utilized by cells to adapt to endoplasmic reticulum (ER) stress. However, the mechanisms of p53 destabilization by ER stress are not known. We demonstrate here that the E3 ubiquitin-ligase Hdm2 is essential for the nucleocytoplasmic transport and p...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/MCB.25.21.9392-9405.2005

    authors: Pluquet O,Qu LK,Baltzis D,Koromilas AE

    更新日期:2005-11-01 00:00:00

  • Glycosylation and secretion of human tissue plasminogen activator in recombinant baculovirus-infected insect cells.

    abstract::Cell lines established from the lepidopteran insect Spodoptera frugiperda (fall armyworm; Sf9) are used routinely as hosts for the expression of foreign proteins by recombinant baculovirus vectors. We have examined the pathway of protein glycosylation and secretion in these cells, using human tissue plasminogen activa...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.9.1.214

    authors: Jarvis DL,Summers MD

    更新日期:1989-01-01 00:00:00

  • Immunologically distinct p53 molecules generated by alternative splicing.

    abstract::Transfection of a functional cloned p53 gene into an L12 p53 nonproducer cell line efficiently reconstituted p53 expression. The p53 protein synthesized in these clones was indistinguishable from that occurring naturally in tumor cells. When a p53 cDNA clone was used instead, we observed that the L12-derived clones ex...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.6.9.3232

    authors: Arai N,Nomura D,Yokota K,Wolf D,Brill E,Shohat O,Rotter V

    更新日期:1986-09-01 00:00:00

  • Bradykinin B(2) receptor-mediated mitogen-activated protein kinase activation in COS-7 cells requires dual signaling via both protein kinase C pathway and epidermal growth factor receptor transactivation.

    abstract::The signaling routes linking G-protein-coupled receptors to mitogen-activated protein kinase (MAPK) may involve tyrosine kinases, phosphoinositide 3-kinase gamma (PI3Kgamma), and protein kinase C (PKC). To characterize the mitogenic pathway of bradykinin (BK), COS-7 cells were transiently cotransfected with the human ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.19.8.5289

    authors: Adomeit A,Graness A,Gross S,Seedorf K,Wetzker R,Liebmann C

    更新日期:1999-08-01 00:00:00

  • An intronic locus control region plays an essential role in the establishment of an autonomous hepatic chromatin domain for the human vitamin D-binding protein gene.

    abstract::The human vitamin D-binding protein (hDBP) gene exists in a cluster of four liver-expressed genes. A minimal hDBP transgene, containing a defined set of liver-specific DNase I hypersensitive sites (HSs), is robustly expressed in mouse liver in a copy-number-dependent manner. Here we evaluate these HSs for function. De...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/MCB.00331-07

    authors: Hiroki T,Liebhaber SA,Cooke NE

    更新日期:2007-11-01 00:00:00

  • Facilitated nucleocytoplasmic shuttling of the Ran binding protein RanBP1.

    abstract::The Ran binding protein RanBP1 is localized to the cytosol of interphase cells. A leucine-rich nuclear export signal (NES) near the C terminus of RanBP1 is essential to maintain this distribution. We now show that RanBP1 accumulates in nuclei of cells treated with the export inhibitor, leptomycin B, and collapse of th...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.20.10.3510-3521.2000

    authors: Plafker K,Macara IG

    更新日期:2000-05-01 00:00:00

  • Biochemical and functional analyses of a secreted H-2Ld molecule.

    abstract::A truncated H-2Ld gene was constructed by deleting the transmembrane and cytoplasmic exons. The truncated H-2Ld gene was introduced into mouse L cells using the thymidine kinase gene as a selectable marker. Transformants were isolated and screened for the presence of truncated H-2Ld antigen. The truncated H-2Ld gene p...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.6.4.1315

    authors: Murre C,Parker KC,Reiss CS,Driller JP,Wiley DC,Burakoff SJ,Seidman JG

    更新日期:1986-04-01 00:00:00

  • Commitment and effector phases of the physiological cell death pathway elucidated with respect to Bcl-2 caspase, and cyclin-dependent kinase activities.

    abstract::Physiological cell deaths occur ubiquitously throughout biology and have common attributes, including apoptotic morphology with mitosis-like chromatin condensation and prelytic genome digestion. The fundamental question is whether a common mechanism of dying underlies these common hallmarks of death. Here we describe ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.18.5.2912

    authors: Harvey KJ,Blomquist JF,Ucker DS

    更新日期:1998-05-01 00:00:00

  • 5'-flanking sequence required for regulated expression of a muscle-specific Drosophila melanogaster actin gene.

    abstract::We have functionally tested derivatives of a muscle-specific Drosophila melanogaster actin gene in which 5'-flanking sequences have been deleted or rearranged. From our results we conclude that approximately 1,000 nucleotides of 5'-flanking sequence are required for wild-type levels of mRNA accumulation during flight ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.6.10.3388

    authors: Geyer PK,Fyrberg EA

    更新日期:1986-10-01 00:00:00

  • p300 and PCAF act cooperatively to mediate transcriptional activation from chromatin templates by notch intracellular domains in vitro.

    abstract::Ligand activation of Notch receptors leads to release of the intracellular receptor domain (Notch IC), which translocates to the nucleus and interacts with the DNA-binding protein RBP-Jkappa to control expression of specific target genes. A number of proteins have been shown to interact with Notch ICs and to modulate ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.22.22.7812-7819.2002

    authors: Wallberg AE,Pedersen K,Lendahl U,Roeder RG

    更新日期:2002-11-01 00:00:00

  • Induction of specific transcription by RNA polymerase III in transformed cells.

    abstract::RNA polymerase III (pol III) transcripts of the highly repeated mouse B2 gene family are increased in many oncogenically transformed murine cell lines. In cells transformed by simian virus 40, the small, cytoplasmic B2 RNAs are present at 20-fold-higher levels than in normal cells (M. R. D. Scott, K. Westphal, and P. ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.6.9.3068

    authors: Carey MF,Singh K,Botchan M,Cozzarelli NR

    更新日期:1986-09-01 00:00:00

  • Preparation of a "functional library" of African green monkey DNA fragments which substitute for the processing/polyadenylation signal in the herpes simplex virus type 1 thymidine kinase gene.

    abstract::Fragments of African green monkey (Cercopithecus aethiops) DNA (3.5 to 18.0 kilobases) were inserted downstream from the thymidine kinase (TK, tk) coding region in pTK206/SV010, a gene construct which lacks both copies of the hexanucleotide 5'-AATAAA-3' and contains a simian virus 40 origin of replication, allowing it...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.3.4.643

    authors: Santangelo GM,Cole CN

    更新日期:1983-04-01 00:00:00

  • Isolation and characterization of cloned DNA sequences containing ribosomal protein genes of Drosophila melanogaster.

    abstract::Ribosomal (r) proteins encoded by polyadenylated RNA were specifically precipitated in vitro from polysomes by using antibodies raised against characterized Drosophila melanogaster r proteins. The immuno-purified mRNA in the polysome complex was used to prepare cDNA with which to probe a D. melanogaster genomic librar...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.4.12.2643

    authors: Burns DK,Stark BC,Macklin MD,Chooi WY

    更新日期:1984-12-01 00:00:00

  • A splice junction deletion deficient in the transport of RNA does not polyadenylate nuclear RNA.

    abstract::A late region deletion mutant of simian virus 40 (dl5) was previously shown to be deficient in the transport of nuclear RNA. This is a splice junction deletion that has lost the 3' end of an RNA leader, an intervening sequence, and the 5' end of the splice acceptor site on the body of the mRNA. In this report, we anal...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.3.8.1381

    authors: Villarreal LP,White RT

    更新日期:1983-08-01 00:00:00

  • ATR1, a Saccharomyces cerevisiae gene encoding a transmembrane protein required for aminotriazole resistance.

    abstract::In Saccharomyces cerevisiae, 3-amino-1,2,4-triazole (aminotriazole) competitively inhibits the activity of imidazoleglycerolphosphate dehydratase, the product of the HIS3 gene. Wild-type strains are able to grow in the presence of 10 mM aminotriazole because they induce the level of imidazoleglycerolphosphate dehydrat...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.8.2.664

    authors: Kanazawa S,Driscoll M,Struhl K

    更新日期:1988-02-01 00:00:00

  • Requirement for a functional interaction between mediator components Med6 and Srb4 in RNA polymerase II transcription.

    abstract::Regulated transcription of class II genes of the yeast Saccharomyces cerevisiae requires the diverse functions of mediator complex. In particular, MED6 is essential for activated transcription from many class II promoters, suggesting that it functions as a key player in the relay of activator signals to the basal tran...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.18.9.5364

    authors: Lee YC,Kim YJ

    更新日期:1998-09-01 00:00:00

  • Mitogenic signaling by colony-stimulating factor 1 and ras is suppressed by the ets-2 DNA-binding domain and restored by myc overexpression.

    abstract::The activity of p21ras is required for the proliferative response to colony-stimulating factor 1 (CSF-1), and signals transduced by both the CSF-1 receptor (CSF-1R) and p21ras stimulate transcription from promoter elements containing overlapping binding sites for Fos/Jun- and Ets-related proteins. A sequence encoding ...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.12.12.5355

    authors: Langer SJ,Bortner DM,Roussel MF,Sherr CJ,Ostrowski MC

    更新日期:1992-12-01 00:00:00

  • Adenovirus E1a ras cooperation activity is separate from its positive and negative transcription regulatory functions.

    abstract::The E1a gene of adenovirus encodes two proteins, 289 and 243 amino acids long, which have positive (transactivator) and negative (enhancer repressor) RNA polymerase II transcriptional regulatory properties and cell transformation activities including cooperation with an activated ras gene. The E1a transforming functio...

    journal_title:Molecular and cellular biology

    pub_type: 杂志文章

    doi:10.1128/mcb.8.5.2177

    authors: Velcich A,Ziff E

    更新日期:1988-05-01 00:00:00