p62/SQSTM1 Enhances NOD2-Mediated Signaling and Cytokine Production through Stabilizing NOD2 Oligomerization

Park, Sangwook; Ha, Soon-Duck; Coleman, Macon D.; Meshkibaf, Shahab; Kim, Sung Ouk

doi:10.1371/journal.pone.0057138

Cited by 27 publications

(18 citation statements)

References 65 publications

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“…When autophagy fails, p62 accumulates in perinuclear inclusions in several neurodegenerative diseases, as well as in macular RPE of AMD samples[4, 10, 46, 47]. If this accumulation is composed predominantly of isoform1, as our results suggest, then this accumulation could foster an Nrf2 cytoprotective response and induce unwanted NF-kB mediated inflammation, including the production of pro-inflammatory cytokines IL-1b and TNF-alpha[48]. On the other hand, if there would be an accumulation of isoform2, then the accumulation could induce Nrf2 signaling without activating NF-kB mediated inflammation.…”

Section: Discussionmentioning

confidence: 97%

p62 provides dual cytoprotection against oxidative stress in the retinal pigment epithelium

Wang¹,

Cano²,

Handa³

2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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As a signaling hub, p62/sequestosome plays important roles in cell signaling and degradation of misfolded proteins. p62 has been implicated as an adaptor protein to mediate autophagic clearance of insoluble protein aggregates in age-related diseases, including age-related macular degeneration (AMD), which is characterized by dysfunction of the retinal pigment epithelium (RPE). Our previous studies have shown that cigarette smoke (CS) induces oxidative stress and inhibits the proteasome pathway in cultured human RPE cells, suggesting that p62-mediated autophagy may become the major route to remove impaired proteins under such circumstances. In the present studies, we found that all p62 mRNA variants are abundantly expressed and upregulated by CS induced stress in cultured human RPE cells, yet isoform1 is the major translated form. We also show that p62 silencing exacerbated the CS induced accumulation of damaged proteins, both by suppressing autophagy and by inhibiting the Nrf2 antioxidant response, which in turn, increased protein oxidation. These effects of CS and p62 reduction were further confirmed in mice exposed to CS. We found that over-expression of p62 isoform1, but not its S403A mutant, which lacks affinity for ubiquitinated proteins, reduced misfolded proteins, yet simultaneously promoted an Nrf2-mediated antioxidant response. Thus, p62 provides dual, reciprocal enhancing protection to RPE cells from environmental stress induced protein misfolding and aggregation, by facilitating autophagy and the Nrf2 mediated antioxidant response, which might be a potential therapeutic target against AMD.

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Section: Discussionmentioning

confidence: 97%

p62 provides dual cytoprotection against oxidative stress in the retinal pigment epithelium

Wang¹,

Cano²,

Handa³

2014

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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“…In this process, NOD2 in conjunction with NOD1 recruits ATG16L1 to the site of bacterial entry to target the forming phagosome to the autophagy machinery [27]. Interestingly, p62 forms a complex with NOD2 and increases NOD2 signaling by stabilizing NOD2 oligomerization [28]. In the intestines, the NLRP6 inflammasome is important for mucus secretion by globlet cells.…”

Section: Crosstalk Between Autophagy and The Inflammasome Machineriesmentioning

confidence: 99%

Checks and Balances between Autophagy and Inflammasomes during Infection

Seveau

Turner

Gavrilin

et al. 2018

Journal of Molecular Biology

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Autophagy and inflammasome complex assembly are physiological processes that control homeostasis, inflammation, and immunity. Autophagy is a ubiquitous pathway that degrades cytosolic macromolecules or organelles, as well as intracellular pathogens. Inflammasomes are multi-protein complexes that assemble in the cytosol of cells upon detection of pathogen- or danger-associated molecular patterns. A critical outcome of inflammasome assembly is the activation of the serine protease caspase-1, which activates the pro-inflammatory cytokine precursors pro-IL-1β and pro-IL-18. Studies on chronic inflammatory diseases, heart diseases, Alzheimer's disease, and multiple sclerosis revealed that autophagy and inflammasomes intersect and regulate each other. In the context of infectious diseases, however, less is known about the interplay between autophagy and inflammasome assembly, although it is becoming evident that pathogens have evolved multiple strategies to inhibit and/or subvert these pathways and to take advantage of their intricate crosstalk. An improved appreciation of these pathways and their subversion by diverse pathogens is expected to help in the design of anti-infective therapeutic interventions.

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“…Resuspended mixtures were centrifuged at 15,500 ϫ g for 10 min, and supernatants were collected (tube B). Tube A and B were combined and used for immunoprecipitation, as described previously (38,55). Briefly, total lysates were mixed with anti-HDAC8 or anti-EGFP antibody and rotated for 4 h at 4°C.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of Interleukin 1β (IL-1β) Expression by Anthrax Lethal Toxin (LeTx) Is Reversed by Histone Deacetylase 8 (HDAC8) Inhibition in Murine Macrophages

Reid

Meshkibaf

et al. 2016

Journal of Biological Chemistry

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Many pathogenic microbes often release toxins that subvert the host's immune responses to render the environment suitable for their survival and proliferation. LeTx is one of the toxins causing immune paralysis by cleaving and inactivating the mitogen-activated protein kinase (MAPK) kinases (MEKs). Here, we show that inhibition of the histone deacetylase 8 (HDAC8) by either the HDAC8-specific inhibitor PCI-34051 or small interference (si)RNAs rendered LeTx-exposed murine macrophages responsive to LPS in pro-IL-1␤ production. HDAC8 selectively targeted acetylated histone H3 lysine 27 (H3K27Ac), which is known to associate with active enhancers. LeTx induced HDAC8 expression, in part through inhibiting p38 MAPK, which resulted in a decrease of H3K27Ac levels. Inhibition of HDAC8 increased H3K27Ac levels and enhanced NF-B-mediated pro-IL-1␤ enhancer and messenger RNA production in LeTx-exposed macrophages. Collectively, this study demonstrates a novel role of HDAC8 in LeTx immunotoxicity and regulation of pro-IL-1␤ production likely through eRNAs. Targeting HDAC8 could be a strategy for enhancing immune responses in macrophages exposed to LeTx or other toxins that inhibit MAPKs.

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p62/SQSTM1 Enhances NOD2-Mediated Signaling and Cytokine Production through Stabilizing NOD2 Oligomerization

Cited by 27 publications

References 65 publications

p62 provides dual cytoprotection against oxidative stress in the retinal pigment epithelium

p62 provides dual cytoprotection against oxidative stress in the retinal pigment epithelium

Checks and Balances between Autophagy and Inflammasomes during Infection

Inhibition of Interleukin 1β (IL-1β) Expression by Anthrax Lethal Toxin (LeTx) Is Reversed by Histone Deacetylase 8 (HDAC8) Inhibition in Murine Macrophages

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