The ubiquitin-binding adaptor proteins p62/SQSTM1 and NDP52 are recruited independently to bacteria-associated microdomains to target Salmonella to the autophagy pathway

Cemma, Marija; Kim, Peter K.; Brumell, John H.

doi:10.4161/auto.7.3.14046

Cited by 179 publications

(188 citation statements)

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“…It can bind both LC3 and ubiquitinated proteins through the LC3 interaction region and ubiquitin-associated domain, respectively (11,14). NDP52 is another cargo marker that drives certain bacteria to the autophagy machinery (9,41). In this study, we found that NDP52 facilitates autophagy uptake of B. cepacia in ⌬F508 macrophages but not in WT cells.…”

Section: Discussionsupporting

confidence: 48%

Depletion of the Ubiquitin-binding Adaptor Molecule SQSTM1/p62 from Macrophages Harboring cftr ΔF508 Mutation Improves the Delivery of Burkholderia cenocepacia to the Autophagic Machinery

Abdulrahman

Khweek

Akhter

et al. 2013

Journal of Biological Chemistry

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Background: Cystic fibrosis is characterized by defective autophagy and increased Burkholderia cenocepacia infection. Results:The depletion of SQSTM1/p62 from ⌬F508 macrophages improves bacterial clearance via autophagy. Conclusion: p62 expression level determines the fate of B. cepacia infection in ⌬F508 macrophages. Significance: Our study reveals the role of p62 in diseases characterized by protein aggregates that compromise autophagy by consuming essential autophagy molecules.

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Section: Discussionsupporting

confidence: 48%

Depletion of the Ubiquitin-binding Adaptor Molecule SQSTM1/p62 from Macrophages Harboring cftr ΔF508 Mutation Improves the Delivery of Burkholderia cenocepacia to the Autophagic Machinery

Abdulrahman

Khweek

Akhter

et al. 2013

Journal of Biological Chemistry

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“…1B,C). A possible explanation for this observation is that p62 and NBR1 mediate independent but parallel peroxisome degradation pathways, like that found with NDP52 and p62 in S. typhimurium (Cemma et al, 2011). Conversely, both may be involved in the same pathway but at different stages.…”

Section: Nbr1 Is Required For the Turnover Of Peroxisomesmentioning

confidence: 87%

“…Interestingly, the colocalization of p62 with NBR1 was only partial as there were distinct NBR1 and p62 structures juxtaposed to each other around peroxisomes. These structures may be analogous to the microdomains formed by the autophagy receptors p62 and NDP52 around Salmonella inside autophagosomes (Cemma et al, 2011;Mostowy et al, 2011;Zheng et al, 2009). However, the nature of these microdomains is not known.…”

Section: Discussionmentioning

confidence: 99%

“…For example, both p62 and NBR1 have been reported to act cooperatively to target polyubiquitylated aggregates to autophagosomes . However, Salmonella targeting to autophagosomes does not require NBR1, but instead requires both p62 and NDP52 (Cemma et al, 2011;Zheng et al, 2009). These two autophagy receptors do not act cooperatively but appear to be recruited to Salmonella independently of each other.…”

Section: Introductionmentioning

confidence: 99%

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NBR1 acts as an autophagy receptor for peroxisomes

Deosaran

Larsen

Hua

et al. 2012

Journal of Cell Science

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SummarySelective macro-autophagy is an intracellular process by which large cytoplasmic materials are selectively sequestered and degraded in the lysosomes. Substrate selection is mediated by ubiquitylation and recruitment of ubiquitin-binding autophagic receptors such as p62, NBR1, NDP52 and Optineurin. Although it has been shown that these receptors act cooperatively to target some types of substrates to nascent autophagosomes, their precise roles are not well understood. We examined selective autophagic degradation of peroxisomes (pexophagy), and found that NBR1 is necessary and sufficient for pexophagy. Mutagenesis studies of NBR1 showed that the amphipathic a-helical J domain, the ubiquitin-associated (UBA) domain, the LC3-interacting region and the coiled-coil domain are necessary to mediate pexophagy. Strikingly, substrate selectivity is partly achieved by NBR1 itself by coincident binding of the J and UBA domains to peroxisomes. Although p62 is not required when NBR1 is in excess, its binding to NBR1 increases the efficiency of NBR1-mediated pexophagy. Together, these results suggest that NBR1 is the specific autophagy receptor for pexophagy.

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“…Therefore Listeria evades both septin caging and autophagy via its surface expression of ActA (11). Given these fundamental differences between Shigella and Listeria, it is clear that in-depth investigation of these two bacteria will help to describe precisely the coordination among actin, septin, and selective autophagy.The role of p62 and/or NDP52 in selective autophagy of Salmonella enterica serovar Typhimurium (S. typhimurium) has recently been characterized (9,14,15). It has been proposed that p62 and NDP52 act independently to drive efficient bacterial autophagy of S. typhimurium within Salmonella-containing vacuoles (15).…”

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confidence: 99%

p62 and NDP52 Proteins Target Intracytosolic Shigella and Listeria to Different Autophagy Pathways

Mostowy

Sancho‐Shimizu

Hamon

et al. 2011

Journal of Biological Chemistry

267

280

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Autophagy is an important mechanism of innate immune defense. We have recently shown that autophagy components are recruited with septins, a new and increasingly characterized cytoskeleton component, to intracytosolic Shigella that have started to polymerize actin. On the other hand, intracytosolic Listeria avoids autophagy recognition by expressing ActA, a bacterial effector required for actin polymerization. Here, we exploit Shigella and Listeria as intracytosolic tools to characterize different pathways of selective autophagy. We show that the ubiquitin-binding adaptor proteins p62 and NDP52 target Shigella to an autophagy pathway dependent upon septin and actin. In contrast, p62 or NDP52 targets the Listeria ActA mutant to an autophagy pathway independent of septin or actin. TNF-␣, a host cytokine produced upon bacterial infection, stimulates p62-mediated autophagic activity and restricts the survival of Shigella and the Listeria ActA mutant. These data provide a new molecular framework to understand the emerging complexity of autophagy and its ability to achieve specific clearance of intracytosolic bacteria.Autophagy is an evolutionarily conserved catabolic pathway that allows eukaryotes to degrade and recycle intracellular components by sequestering proteins and organelles in specialized double-membrane vesicles named autophagosomes (1-3). Although autophagosomes can sequester cytosolic material nonspecifically, e.g. as a response to starvation, there is increasing evidence for selective autophagic degradation of various cellular structures, including protein aggregates, mitochondria, and microbes (4, 5). The mechanism of selective autophagy is not well understood, yet the role of ubiquitin in this process is critical (5, 6). By simultaneous binding to both ubiquitin and the autophagosome-associated ubiquitin-like proteins (i.e. LC3/GABARAP proteins) autophagy receptors can mediate docking of ubiquitinated cargo to the autophagosome, thereby ensuring their selective degradation (5, 6). Of the ubiquitinbinding proteins in selective autophagy, p62 (sequestosome 1; SQSTM1) has emerged as the prototype autophagy receptor (7). p62 is an LC3 interaction partner in vivo and is constantly degraded by autophagy, establishing it as a useful marker for autophagic vesicle turnover (8). NDP52 3 has more recently emerged as another autophagy receptor and shares with p62 the ability to bind LC3 and ubiquitinated cargo simultaneously (9). The respective roles of p62 and NDP52 are not understood. Whether these individual autophagy receptors recognize different ubiquitinated proteins and/or perform independent functions in cells may be critical for the complete understanding of autophagy and its therapeutic potential.Recent evidence has implicated the cytoskeleton as a critical mediator of selective autophagy. We have shown that septins, a novel component of the cytoskeleton (10), are recruited with autophagy proteins to "cage" Shigella flexneri in the cytosol of infected cells and restrict bacterial dissemination (11). The...

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The ubiquitin-binding adaptor proteins p62/SQSTM1 and NDP52 are recruited independently to bacteria-associated microdomains to target Salmonella to the autophagy pathway

Cited by 179 publications

References 18 publications

Depletion of the Ubiquitin-binding Adaptor Molecule SQSTM1/p62 from Macrophages Harboring cftr ΔF508 Mutation Improves the Delivery of Burkholderia cenocepacia to the Autophagic Machinery

Depletion of the Ubiquitin-binding Adaptor Molecule SQSTM1/p62 from Macrophages Harboring cftr ΔF508 Mutation Improves the Delivery of Burkholderia cenocepacia to the Autophagic Machinery

NBR1 acts as an autophagy receptor for peroxisomes

p62 and NDP52 Proteins Target Intracytosolic Shigella and Listeria to Different Autophagy Pathways

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