Atg16l1 in dendritic cells is required for antibacterial defense and autophagy in murine colitis

Zhang, Hong; Wang, Dong; Shihb, David Q; Zhang, Xiaolan

doi:10.1002/iub.2406

Cited by 8 publications

(6 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Membrane localized GRP78 is capable of sensing the presence of denatured Tau and APP in the extracellular space liminal to the plasma membrane of neurons and microglia. Extracellular GRP78 chaperones both Tau and APP and extracellular GRP78 is essential for amyloid-β uptake by microglia [50][51][52][53][54][55][56]. Previously we noted that cells expressing ATG16L1 T300 expressed Figure 16.…”

Section: Discussionmentioning

confidence: 94%

AR12 increases BAG3 expression which is essential for Tau and APP degradation via LC3-associated phagocytosis and macroautophagy

Dent

Booth

Roberts

et al. 2022

Aging

View full text Add to dashboard Cite

We defined the mechanisms by which the chaperone ATPase inhibitor AR12 and the multi-kinase inhibitor neratinib interacted to reduce expression of Tau and amyloid-precursor protein (APP) in microglia and neuronal cells. AR12 and neratinib interacted to increase the phosphorylation of eIF2A S51 and the expression of BAG3, Beclin1 and ATG5, and in parallel, enhanced autophagosome formation and autophagic flux. Knock down of BAG3, Beclin1 or ATG5 abolished autophagosome formation and significantly reduced degradation of p62, LAMP2, Tau, APP, and GRP78 (total and plasma membrane). Knock down of Rubicon, a key component of LC3-associated phagocytosis (LAP), significantly reduced autophagosome formation but not autophagic flux and prevented degradation of Tau, APP, and cell surface GRP78, but not ER-localized GRP78. Knock down of Beclin1, ATG5 or Rubicon or over-expression of GRP78 prevented the significant increase in eIF2A phosphorylation. Knock down of eIF2A prevented the increase in BAG3 expression and significantly reduced autophagosome formation, autophagic flux, and it prevented Tau and APP degradation. We conclude that AR12 has the potential to reduce Tau and APP levels in neurons and microglia via the actions of LAP, endoplasmic reticulum stress signaling and macroautophagy. We hypothesize that the initial inactivation of GRP78 catalytic function by AR12 facilitates an initial increase in eIF2A phosphorylation which in turn is essential for greater levels of eIF2A phosphorylation, greater levels of BAG3 and macroautophagy and eventually leading to significant amounts of APP/Tau degradation.

show abstract

Section: Discussionmentioning

confidence: 94%

AR12 increases BAG3 expression which is essential for Tau and APP degradation via LC3-associated phagocytosis and macroautophagy

Dent

Booth

Roberts

et al. 2022

Aging

View full text Add to dashboard Cite

show abstract

“…Previous studies showed that following stimulation with LPS, Atg16L1-deficient macrophages produce high amounts of inflammatory cytokines IL-1 β and IL-18 [ 19 , 20 ]. They subsequently found that mice lacking Atg16L1 in hematopoietic cells are highly susceptible to dextran sulfate sodium- (DSS-) induced acute colitis [ 21 , 22 ]. Our present study indicates that rapamycin-induced autophagy significantly alleviates experimental colitis and decreases the TNF- α secretion from LPS-induced HT-29 cells, which were in accordance with the previous studies.…”

Section: Discussionmentioning

confidence: 99%

Rapamycin Alleviates 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis through Autophagy Induction and NF-κB Pathway Inhibition in Mice

Zhen¹,

Li²,

Mu³

et al. 2022

Mediators of Inflammation

View full text Add to dashboard Cite

Background. Recent genetic studies indicated that variants of autophagy genes were associated with the predisposition of Crohn’s disease (CD). The autophagy deficiency may affect the innate and adaptive immunity, which is related to persistent and excessive inflammation of the bowel. However, it remains unclear how autophagy modulates the expression of immune response regulator NF-κB and proinflammatory cytokine TNF-α in CD. Aim. We aimed to investigate the role of rapamycin on the expression of NF-κB p65 and TNF-α in 2, 4, 6-trinitrobenzene sulfonic acid (TNBS)-induced mouse colitis and lipopolysaccharide (LPS)-induced HT-29 cells. Methods. TNBS-induced colitis mice were treated with saline or rapamycin, and the disease activity index (DAI) and histological scores of colonic mucosa were evaluated. The expressions of p65, ATG16L1 and LC3 were detected by western blot and immunohistochemistry staining. The monodansylcadaverine (MDC) staining and transmission electron microscopy were developed to study the autophagy in LPS-induced HT-29 cells. Expression of TNF-α from colon tissue and HT-29 cells were detected by ELISA. The expressions of p65, ATG16L1 and LC3 in active CD patients were also investigated. Results. Significantly more autophagosomes were observed in rapamycin-treated cells than in controls. Rapamycin remarkably upregulated the expression of ATG16L1 and LC3II, inhibited p65 nucleus translocation and secretion of TNF-α both in vivo and in vitro. The expression of both ATG16L1 and LC3II increased in mild to moderate CD specimens, while no significant difference was noted between severe CD and normal controls. The expression of p65 increased notably in severe CD compared to those in mild to moderate patients. Conclusions. In LPS-treated HT-29 cells and TNBS-induced colitis, p65 is overexpressed, which results in exaggerated secretion of TNF-α and induce or worsen the inflammation in the bowel. Rapamycin protects against colitis through induction of autophagy, thus inhibiting the activation of NF-κB pathway and secretion of TNF-α.

show abstract

“…Membrane localized GRP78 is capable of sensing the presence of denatured Tau and APP in the extracellular space liminal to the plasma membrane of neurons and microglia. Extracellular GRP78 chaperones both Tau and APP and extracellular GRP78 is essential for amyloid-b uptake by microglia [48][49][50][51][52][53][54]. Previously we noted that cells expressing ATG16L1 T300 expressed 25% higher cell surface levels of GRP78 than cells expressing ATG16L1 A300 [10].…”

Section: Discussionmentioning

confidence: 99%

AR12 increases BAG3 expression via ER stress signaling which is essential for Tau and APP degradation via LC3-associated phagocytosis and macroautophagy

Dent

Booth

Roberts

et al. 2022

Preprint

View full text Add to dashboard Cite

Background We defined the mechanisms by which the chaperone ATPase inhibitor AR12 and the multi-kinase inhibitor neratinib interacted to reduce expression of Tau and amyloid-precursor protein (APP) in microglia and neuronal cells. Methods In vitro cell culture; in-cell immunostaining using a Hermes wide-field microscope with densitometric imaging software; transfection of siRNA and plasmids; assessments of autophagy using a plasmid to express LC3-GFP-RFP. Results AR12 and neratinib interacted to increase the phosphorylation of eIF2A S51 and the expression of BAG3, Beclin1 and ATG5, and in parallel, enhanced autophagosome formation and autophagic flux. Knock down of BAG3, Beclin1 or ATG5 abolished autophagosome formation and significantly reduced degradation of p62, LAMP2, Tau, APP, and GRP78 (total and plasma membrane). Knock down of Rubicon, a key component of LC3-associated phagocytosis (LAP), significantly reduced autophagosome formation but not autophagic flux and prevented degradation of Tau, APP, and cell surface GRP78, but not ER-localized GRP78. Knock down of Beclin1, ATG5 or Rubicon or over-expression of GRP78 prevented the significant increase in eIF2A phosphorylation. Knock down of eIF2A prevented the increase in BAG3 expression and significantly reduced autophagosome formation, autophagic flux, and it prevented Tau and APP degradation. Conclusions We conclude that AR12 has the potential to reduce Tau and APP levels in neurons and microglia via the actions of LAP, endoplasmic reticulum stress signaling and macroautophagy. We hypothesize that the initial inactivation of GRP78 catalytic function by AR12 facilitates an initial increase in eIF2A phosphorylation which in turn is essential for greater levels of eIF2A phosphorylation, greater levels of BAG3 and macroautophagy and eventually leading to significant amounts of APP/Tau degradation.

show abstract

Atg16l1 in dendritic cells is required for antibacterial defense and autophagy in murine colitis

Cited by 8 publications

References 41 publications

AR12 increases BAG3 expression which is essential for Tau and APP degradation via LC3-associated phagocytosis and macroautophagy

AR12 increases BAG3 expression which is essential for Tau and APP degradation via LC3-associated phagocytosis and macroautophagy

Rapamycin Alleviates 2,4,6-Trinitrobenzene Sulfonic Acid-Induced Colitis through Autophagy Induction and NF-κB Pathway Inhibition in Mice

AR12 increases BAG3 expression via ER stress signaling which is essential for Tau and APP degradation via LC3-associated phagocytosis and macroautophagy

Contact Info

Product

Resources

About