COP9 Signalosome Regulates Autophagosome Maturation

Su, Huabo; Li, Faqian; Ranek, Mark J.; Wei, Ning; Wang, Xuejun

doi:10.1161/circulationaha.111.048934

Cited by 100 publications

(114 citation statements)

References 24 publications

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“…These results argue against the possibility that accumulation of AVs and ubiquitinated protein aggregates stems from a failure of autophagosome removal due to impaired lysosome biogenesis or autophagosome maturation, the disruption of which has been linked to cell death (42). Together, these findings indicate that coadministration of a Cdk inhibitor with an autophagy-inducing BH3 mimetic triggers inefficient autophagy characterized by an impaired ability of cells to clear ubiquitinated, malfolded proteins.…”

Section: Resultsmentioning

confidence: 93%

Targeting SQSTM1/p62 Induces Cargo Loading Failure and Converts Autophagy to Apoptosis via NBK/Bik

Chen

Zhou

Zhang

et al. 2014

Molecular and Cellular Biology

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eIn 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 timedependent 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.A utophagy is an evolutionarily conserved process by which damaged organelles and unneeded proteins are degraded by lysosomes to maintain intracellular homeostasis and to recycle cellular nutrients. While autophagy can promote cell death (1), in most cases, it is cytoprotective and contributes to drug resistance (2). In response to chemotherapeutic agents, apoptosis (type I) and autophagy (type II) represent two major forms of programmed cell death (3). Autophagy and apoptosis share molecular regulatory mechanisms governed by Bcl-2 family proteins (3, 4). Specifically, Bcl-2 and Bcl-x L prevent both apoptosis and autophagy by sequestering different BH3-only proteins (e.g., proapoptotic Bim and Bid [5] and proautophagic beclin-1 [6,7]). As a result, antagonism of Bcl-2/Bcl-x L function releases and activates these BH3-only proteins, leading to apoptosis and autophagy, respectively (8). While apoptosis represents a well-established mechanism of action of conventional and targeted anticancer agents (3), autophagy may play both positive and negative roles in tumorigenesis and cancer treatment (9, 10). Consequently, whether autophagy should be inhibited or activated remains the subject of debate. Accordingly, both autophagy inhibitors and inducers are currently undergoing clinical evaluation (11).Protection of cells from injury by harmful macromolecules or damaged organelles through autophagy as a quality control (QC) mechanism (11, 12) involves the sequestration and tran...

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Section: Resultsmentioning

confidence: 93%

Targeting SQSTM1/p62 Induces Cargo Loading Failure and Converts Autophagy to Apoptosis via NBK/Bik

Chen

Zhou

Zhang

et al. 2014

Molecular and Cellular Biology

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“…Our results indicate that CSN1 does not cooperate with IFT20 in the regulation of TCR trafficking to the IS but do not rule out a role for this protein in signalling events downstream of TCR stimulation. Recent evidence has implicated the COP9 signalosome in another critical quality control pathway, namely, autophagy (Pearce et al, 2009;Su et al, 2011;Zhang et al, 2016). Remarkably, the IFT system has been shown to participate in the first steps of autophagosome formation in ciliated cells (Pampliega et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

The T cell IFT20 interactome reveals new players in immune synapse assembly

Galgano

Onnis

Pappalardo

et al. 2017

Journal of Cell Science

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Sustained signalling at the immune synapse (IS) requires the synaptic delivery of recycling endosome-associated T cell antigen receptors (TCRs). IFT20, a component of the intraflagellar transport system, controls TCR recycling to the IS as a complex with IFT57 and IFT88. Here, we used quantitative mass spectrometry to identify additional interaction partners of IFT20 in Jurkat T cells. In addition to IFT57 and IFT88, the analysis revealed new binding partners, including IFT54 (also known as TRAF3IP1), GMAP-210 (also known as TRIP11), Arp2/3 complex subunit-3 (ARPC3), COP9 signalosome subunit-1 (CSN1, also known as GPS1) and ERGIC-53 (also known as LMAN1). A direct interaction between IFT20 and both IFT54 and GMAP-210 was confirmed in pulldown assays. Confocal imaging of antigen-specific conjugates using T cells depleted of these proteins by RNA interference showed that TCR accumulation and phosphotyrosine signalling at the IS were impaired in the absence of IFT54, ARPC3 or ERGIC-53. Similar to in IFT20-deficient T cells, this defect resulted from a reduced ability of endosomal TCRs to polarize to the IS despite a correct translocation of the centrosome towards the antigen-presenting cell contact. Our data underscore the traffic-related role of an IFT20 complex that includes components of the intracellular trafficking machinery in IS assembly.

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“…Besides the fact that immunity and SA responses are affected in csn3, csn4, and csn5 mutants, the COP9/signalosome (CSN) complex modulates protein degradation in eukaryotes by regulating the ubiquitin-proteasome system. It was shown in mice that the COP9 signalosome regulates autophagosome maturation (Su et al, 2011). The authors observed the accumulation of immature autophagosomes in csn8 mouse cardiomyocytes.…”

Section: Why Do Autophagy Mutants Overexpress Defense Genes?mentioning

confidence: 97%

Stitching together the Multiple Dimensions of Autophagy Using Metabolomics and Transcriptomics Reveals Impacts on Metabolism, Development, and Plant Responses to the Environment inArabidopsis

et al. 2014

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Autophagy is a fundamental process in the plant life story, playing a key role in immunity, senescence, nutrient recycling, and adaptation to the environment. Transcriptomics and metabolomics of the rosette leaves of Arabidopsis thaliana autophagy mutants (atg) show that autophagy is essential for cell homeostasis and stress responses and that several metabolic pathways are affected. Depletion of hexoses, quercetins, and anthocyanins parallel the overaccumulation of several amino acids and related compounds, such as glutamate, methionine, glutathione, pipecolate, and 2-aminoadipate. Transcriptomic data show that the pathways for glutathione, methionine, raffinose, galacturonate, and anthocyanin are perturbed. Anthocyanin depletion in atg mutants, which was previously reported as a possible defect in flavonoid trafficking to the vacuole, appears due to the downregulation of the master genes encoding the enzymes and regulatory proteins involved in flavonoid biosynthesis. Overexpression of the PRODUCTION OF ANTHOCYANIN PIGMENT1 transcription factor restores anthocyanin accumulation in vacuoles of atg mutants. Transcriptome analyses reveal connections between autophagy and (1) salicylic acid biosynthesis and response, (2) cytokinin perception, (3) oxidative stress and plant defense, and possible interactions between autophagy and the COP9 signalosome machinery. The metabolic and transcriptomic signatures identified for the autophagy mutants are discussed and show consistencies with the observed phenotypes.

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COP9 Signalosome Regulates Autophagosome Maturation

Cited by 100 publications

References 24 publications

Targeting SQSTM1/p62 Induces Cargo Loading Failure and Converts Autophagy to Apoptosis via NBK/Bik

Targeting SQSTM1/p62 Induces Cargo Loading Failure and Converts Autophagy to Apoptosis via NBK/Bik

The T cell IFT20 interactome reveals new players in immune synapse assembly

Stitching together the Multiple Dimensions of Autophagy Using Metabolomics and Transcriptomics Reveals Impacts on Metabolism, Development, and Plant Responses to the Environment inArabidopsis

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