Correction: Endothelial PKA activity regulates angiogenesis by limiting autophagy through phosphorylation of ATG16L1
Xiaocheng ZhaoPavel I. NedvetskyFabio StanchiAnne-Clémence VionOliver PoppKerstin ZühlkeGunnar DittmarEnno KlußmannHolger Gerhardt
0
Citation
72
Reference
10
Related Paper
Abstract:
The cAMP-dependent protein kinase A (PKA) regulates various cellular functions in health and disease.In endothelial cells PKA activity promotes vessel maturation and limits tip cell formation.Here, we used a chemical genetic screen to identify endothelial-specific direct substrates of PKA in human umbilical vein endothelial cells (HUVEC) that may mediate these effects.Amongst several candidates, we identified ATG16L1, a regulator of autophagy, as novel target of PKA. Biochemical validation, mass spectrometry and peptide spot arrays revealed that PKA phosphorylates ATG16L1a at Ser268 and ATG16L1b at Ser269, driving phosphorylationdependent degradation of ATG16L1 protein.Reducing PKA activity increased ATG16L1 protein levels and endothelial autophagy.Mouse in vivo genetics and pharmacological experiments demonstrated that autophagy inhibition partially rescues vascular hypersprouting caused by PKA deficiency.Together these results indicate that endothelial PKA activity mediates a critical switch from active sprouting to quiescence in part through phosphorylation of ATG16L1, which in turn reduces endothelial autophagy.Keywords:
Limiting
ATG16L1
ATG16L1
Cite
Citations (1)
During nutrient deprivation, autophagy provides the constituents required to maintain the metabolism essential for survival. Recently, genome-wide association studies have identified genetic determinants for susceptibility to Crohn's disease (CD) such as ATG16L1 and IRGM that are involved in the autophagy pathway. Both disease-carrying NOD2 mutations and ATG16L1 mutations may result in impairment of autophagy. Impairment in autophagy results in impaired clearance of microbes. Ileal CD is associated with Paneth cell loss of function such as decreased production of α-defensins, which may arise from mutations in NOD2 or autophagy genes. Nutrients are able to modify several cellular pathways and in particular autophagy. We summarize the contribution of a variety of dietary components to activate autophagy. Understanding the crosstalk between nutrients and autophagy in the intestine may provide novel targets that have therapeutics potential in intestinal inflammation. Nutrient activation of autophagy may contribute to restoring the Paneth cell loss of function in ileal CD.
ATG16L1
Crosstalk
Nutrient Sensing
Paneth cell
Cite
Citations (6)
Autophagy is a lysosome-dependent degradative process that protects cancer cells from multiple stresses. In preclinical models, autophagy inhibition with chloroquine (CQ) derivatives augments the efficacy of many anticancer therapies, but CQ has limited activity as a single agent. Clinical trials are underway combining anticancer agents with hydroxychloroquine (HCQ), but concentrations of HCQ required to inhibit autophagy are not consistently achievable in the clinic. We report the synthesis and characterization of bisaminoquinoline autophagy inhibitors that potently inhibit autophagy and impair tumor growth in vivo. The structural motifs that are necessary for improved autophagy inhibition compared with CQ include the presence of two aminoquinoline rings and a triamine linker and C-7 chlorine. The lead compound, Lys01, is a 10-fold more potent autophagy inhibitor than HCQ. Compared with HCQ, Lys05, a water-soluble salt of Lys01, more potently accumulates within and deacidifies the lysosome, resulting in impaired autophagy and tumor growth. At the highest dose administered, some mice develop Paneth cell dysfunction that resembles the intestinal phenotype of mice and humans with genetic defects in the autophagy gene ATG16L1, providing in vivo evidence that Lys05 targets autophagy. Unlike HCQ, significant single-agent antitumor activity is observed without toxicity in mice treated with lower doses of Lys05, establishing the therapeutic potential of this compound in cancer.
ATG16L1
Cite
Citations (383)
ATG16L1
BAG3
Autophagosome
ULK1
Organelle
Cite
Citations (36)
Cite
Citations (195)
Autophagosome
Homeostasis
ATG16L1
Organelle
Cite
Citations (51)
Abstract Autophagy is a highly inducible system of intracellular degradation that occurs in lysosomes or vacuoles. Transmembrane 74 (TMEM74) has been shown to induce autophagy. However, the mechanism by which TMEM74 stimulates autophagy and the impacts of TMEM74-induced autophagy on tumor cell survival remain unclear. In this study, TMEM74 was shown to increase the autophagic flux process in different tumor cell lines. Further investigations revealed that TMEM74 interacts with ATG16L1 and ATG9A. Moreover, distinctive from the common autophagy models, it is found that TMEM74-related autophagy is independent of BECN1/PI3KC3 complex and ULK1, and TMEM74 may initiate and promote autophagy directly via interactions with ATG16L1 and ATG9A responsible for the nucleation and elongation respectively. Considering the ultimate outcome of TMEM74-induced autophagy in tumor cells, TMEM74-triggered autophagy induces a pro-survival effect on tumor cells, particularly cells under metabolic stress, consistent with alteration of a series of signal pathways. Intriguingly, TMEM74 itself can be downregulated through the autophagic process, which indicates that a potential self-regulatory loop exists so as to maintain an appropriate level of autophagy, avoiding excessive autophagy to commit tumor cells to death. According to the clinical database analysis, the high expression of TMEM74 significantly shortens the surviving periods of patients in several specific cancers indicating that TMEM74 itself can be treated as an effective potential target with clinical values to prolong surviving periods of cancer patients in the future. In conclusion, our study reveals a new mechanism by which autophagy is stimulated by a novel positive modulator through a unique pathway and demonstrates a novel connection between autophagy and cell survival, which undoubtedly serves to broaden our understanding of autophagy.
ULK1
ATG16L1
BECN1
Cite
Citations (22)
Autophagy is a main pathway that clears the dysfunction organelles,misfolding proteins and oxidative lipids.It's important for maintaining life activity and conserved from yeast to mammalian.In the AD neurons the misfolding proteins were not efficiently cleared then accumulated.These caused neurons loss of function even neuron death.This review focuses on the recent progresses on regulation of autophagy and the role of autophagy in Alzheimer's diseases.Autophagy is protective in early stage of AD,although it induces autophagic cell death in late stage of AD.Autophagosome may be the main site for Aβ production and clearance.Presenilin 1 which is the key proteinase in γ-secrectase also plays a role in lysosomal acidification which is a key step for autophagic degradation.Tau may be involved in autophagosome trafficking and autophagosome-lysosome fusion.mTOR and AMPK sensing nutrients and energy in cells also regulate autophagy.
Autophagosome
ATG16L1
BAG3
TFEB
ULK1
Cite
Citations (0)
Autophagosome
ATG16L1
Homeostasis
Cite
Citations (0)
Autophagy and phagocytosis are two important processes that capture and digest materials found in cellular interiors and exteriors, respectively. Aged red blood cells (RBCs) are cleared by phagocytes in vivo. We focused on determining whether autophagy occurs after phagocytes swallow sunset erythrocytes, and whether the degree of autophagy is related to scavenging ability of phagocytes to erythrocytes. In addition, the ability of NLR family pyrin domain containing protein 3 (NLRP3) inflammasome to regulate erythrocyte clearance by phagocytes and its association with autophagy-related protein 16-like protein 1 (ATG16L1) are confirmed. We constructed a stable and low-NLRP3 expression THP-1 cell line using CRISPR/Cas9 technology. The analysis of erythrocyte clearance and autophagy of THP-1 cells with low NLRP3 expression showed that autophagy changes together when THP-1 engulfs aged RBCs. The occurrence of autophagy was dominated by microtubule-associated protein 1A/1B-light chain 3- (LC3-) associated phagocytosis accompanied by canonical autophagy. A negative correlation exists between the clearance of RBCs by THP-1 cells and the degree of autophagy. Downregulating the expression of NLRP3 in THP-1 cells can simultaneously inhibit the scavenging ability of THP-1 to erythrocytes and the degree of autophagy. In addition, the autophagy inhibitor bafilomycin A1 (BafA1) can enhance the phagocytosis ability of THP-1 to erythrocytes and promote the NLRP3 activation in THP-1 cells, while the autophagy inducer rapamycin inhibits the phagocytosis ability of THP-1 to RBCs and downregulates the NLRP3 activation. Results showed that autophagy and phagocytosis may be dynamic balance processes that can provide sufficient nutrition and energy to cells. Choosing NLRP3 as a target may regulate the phagocytic ability and the degree of autophagy in the meantime. These findings may be a potential strategy for regulating the clearance rate of phagocytes to aged RBCs and the secretion of proinflammatory cytokines to ensure transfusion safety.
THP1 cell line
ATG16L1
Cite
Citations (3)