Regulated proteolysis of p62/SQSTM1 enables differential control of autophagy and nutrient sensing

Sanchez‐Garrido, Julia; Sancho-Shimizu, Vanessa; Shenoy, Avinash R.

doi:10.1126/scisignal.aat6903

Cited by 34 publications

(31 citation statements)

References 79 publications

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“…The requirement for p62 in TAK1 activation is in line with previous reports of p62 enhancing NF‐κB activation in response to a variety of stimuli , as TAK1 is upstream of NF‐κB. Overall, our findings mirror the results of a recent report in which p62 is switched from autophagy action to a signaling role, albeit by a different mechanism involving caspase 8‐dependent cleavage .…”

Section: Discussionsupporting

confidence: 92%

TAK 1 converts Sequestosome 1/p62 from an autophagy receptor to a signaling platform

et al. 2019

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The protein p62/Sequestosome 1 (p62) has been described as a selective autophagy receptor and independently as a platform for pro‐inflammatory and other intracellular signaling. How these seemingly disparate functional roles of p62 are coordinated has not been resolved. Here, we show that TAK1, a kinase involved in immune signaling, negatively regulates p62 action in autophagy. TAK1 reduces p62 localization to autophagosomes, dampening the autophagic degradation of both p62 and p62‐directed autophagy substrates. TAK1 also relocalizes p62 into dynamic cytoplasmic bodies, a phenomenon that accompanies the stabilization of TAK1 complex components. On the other hand, p62 facilitates the assembly and activation of TAK1 complexes, suggesting a connection between p62's signaling functions and p62 body formation. Thus, TAK1 governs p62 action, switching it from an autophagy receptor to a signaling platform. This ability of TAK1 to disable p62 as an autophagy receptor may allow certain autophagic substrates to accumulate when needed for cellular functions.

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Section: Discussionsupporting

confidence: 92%

TAK 1 converts Sequestosome 1/p62 from an autophagy receptor to a signaling platform

et al. 2019

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“…This contrasts our discovery of the ubiquitin conjugating enzyme UBE2L3 as an indirect target of caspase-1 that specifically control IL-1β production, but not pyroptosis (Eldridge et al, 2017). Studies on cellular targets of caspases may therefore provide new insights on homeostasis and disease (Sanchez-Garrido et al, 2018).…”

Section: Discussionmentioning

confidence: 75%

Human GBP1 differentially targetsSalmonellaandToxoplasmato license recognition of microbial ligands and caspase-mediated death

Fisch

Clough

Domart

et al. 2019

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Human guanylate binding proteins (GBPs), a family of IFNγ-inducible GTPases, promote cell-intrinsic defence against pathogens and host cell death. We previously identified GBP1 as a mediator of cell death of human macrophages infected with Toxoplasma gondii (Tg) or Salmonella Typhimurium (STm). How GBP1 targets microbes for AIM2 activation during Tg infection and caspase-4 during STm infection remains unclear. Here, using correlative light and electron microscopy and EdU labelling of Tg-DNA, we reveal that GBP1-decorated parasitophorous vacuoles (PVs) lose membrane integrity and release Tg-DNA for detection by AIM2-ASC-CASP8. In contrast, differential staining of cytosolic and vacuolar STm revealed that GBP1 does not contribute to STm escape into the cytosol but decorates almost all cytosolic STm leading to the recruitment of caspase-4. Caspase-5, which can bind LPS and whose expression is upregulated by IFNγ, does not target STm pointing to a key role for caspase-4 in pyroptosis. We also uncover a regulatory mechanism involving the inactivation of GBP1 by its cleavage at Asp192 by caspase-1. Cells expressing non-cleavable GBP1 D192E therefore undergo higher caspase-4-driven pyroptosis during STm infection. Taken together, our comparative studies elucidate microbe-specific spatiotemporal roles of GBP1 in inducing cell death by leading to assembly and regulation of divergent caspase signalling platforms.

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“…For immunoblot analyses of proteins in supernatants, proteins were precipitated at −20°C overnight in acetone, air-dried and resuspended in 2X Laemmli loading buffer plus 5% 2ME ( Eldridge et al., 2017 ). Cell extracts were prepared in ice-cold RIPA buffer (60 mM Tris pH 8.0, 150 mM NaCl, 1% NP-40, 0.5% Na-deoxycholate, 1 mM EDTA; all from Sigma) supplemented with complete protease inhibitor tablets, and 1 mM phenylmethylsulfonyl fluoride (PMSF), followed by the addition of 5% 2ME and Laemmli loading buffer( Sanchez-Garrido et al., 2018 ). Pooled culture supernatants and cell extracts were prepared by resuspending air-dried precipitates of supernatants in cell lysates prepared from respective samples.…”

Section: Methodsmentioning

confidence: 99%

Enteropathogenic Escherichia coli Stimulates Effector-Driven Rapid Caspase-4 Activation in Human Macrophages

et al. 2019

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Summary Microbial infections can stimulate the assembly of inflammasomes, which activate caspase-1. The gastrointestinal pathogen enteropathogenic Escherichia coli (EPEC) causes localized actin polymerization in host cells. Actin polymerization requires the binding of the bacterial adhesin intimin to Tir, which is delivered to host cells via a type 3 secretion system (T3SS). We show that EPEC induces T3SS-dependent rapid non-canonical NLRP3 inflammasome activation in human macrophages. Notably, caspase-4 activation by EPEC triggers pyroptosis and cytokine processing through the NLRP3-caspase-1 inflammasome. Mechanistically, caspase-4 activation requires the detection of LPS and EPEC-induced actin polymerization, either via Tir tyrosine phosphorylation and the phosphotyrosine-binding adaptor NCK or Tir and the NCK-mimicking effector TccP. An engineered E. coli K12 could reconstitute Tir-intimin signaling, which is necessary and sufficient for inflammasome activation, ruling out the involvement of other virulence factors. Our studies reveal a crosstalk between caspase-4 and caspase-1 that is cooperatively stimulated by LPS and effector-driven actin polymerization.

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Regulated proteolysis of p62/SQSTM1 enables differential control of autophagy and nutrient sensing

Cited by 34 publications

References 79 publications

TAK 1 converts Sequestosome 1/p62 from an autophagy receptor to a signaling platform

TAK 1 converts Sequestosome 1/p62 from an autophagy receptor to a signaling platform

Human GBP1 differentially targetsSalmonellaandToxoplasmato license recognition of microbial ligands and caspase-mediated death

Enteropathogenic Escherichia coli Stimulates Effector-Driven Rapid Caspase-4 Activation in Human Macrophages

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