Autophagy Induced by Calcium Phosphate Precipitates Targets Damaged Endosomes

Chen, Xi; Khambu, Bilon; Zhang, Hao; Gao, Wentao; Li, Min; Chen, Xiaoyun; Yoshimori, Tamotsu; Yin, Xiao Ming

doi:10.1074/jbc.m113.531855

Cited by 70 publications

(70 citation statements)

References 40 publications

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“…One distinct feature of autophagy is that large cytoplasmic objects such as organelles including surplus peroxisomes [42], excess mitochondria [43], depolarized mitochondria [9, 44], damaged endosomes and lysosomes [45, 46], or invading microbes [10] can be engulfed by autophagosomes. Some of the above autophagy targets, typically associated with degradative autophagy, can also become secretory autophagy cargo [43, 47–49] (Table 1, I-C).…”

Section: Secretory Autophagy and Extracellular Release Of Intracellulmentioning

confidence: 99%

Secretory autophagy

Ponpuak

Mandell

Kimura

et al. 2015

Current Opinion in Cell Biology

421

356

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Autophagy, once viewed exclusively as a cytoplasmic auto-digestive process, has its less intuitive but biologically distinct non-degradative roles. One manifestation of these functions of the autophagic machinery is the process termed secretory autophagy. Secretory autophagy facilitates unconventional secretion of the cytosolic cargo such as leaderless cytosolic proteins, which unlike proteins endowed with the leader (N-terminal signal) peptides cannot enter the conventional secretory pathway normally operating via the endoplasmic reticulum and the Golgi apparatus. Secretory autophagy may also export more complex cytoplasmic cargo and help excrete particulate substrates. Autophagic machinery and autophagy as a process also affect conventional secretory pathways, including the constitutive and regulated secretion, as well as promote alternative routes for trafficking of integral membrane proteins to the plasma membrane. Thus, autophagy and autophagic factors are intimately intertwined at many levels with secretion and polarized sorting in eukaryotic cells.

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Section: Secretory Autophagy and Extracellular Release Of Intracellulmentioning

confidence: 99%

Secretory autophagy

Ponpuak

Mandell

Kimura

et al. 2015

Current Opinion in Cell Biology

421

356

View full text Add to dashboard Cite

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“…We also studied the impact of dynasore, a dynamin inhibitor that participates in autophagosome formation on bortezomib-mediated FLT3-ITD degradation. 26 Dynasore also restored FLT3-ITD expression, but importantly also inhibited bortezomib-induced apoptosis in MV4-11 and MOLM-14 cell lines and patient samples (supplemental Figure 3A-D). These results indicate that in AML cells, bortezomib regulates FLT3-ITD expression at the protein level through autophagy induction.…”

Section: Bortezomib Induces the Degradation Of Flt3-itd Through An Aumentioning

confidence: 99%

Proteasome inhibitors induce FLT3-ITD degradation through autophagy in AML cells

Larrue

Saland

Boutzen

et al. 2016

Blood

110

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Key Points• Bortezomib induces the degradation of FLT3-ITD through an autophagydependent mechanism that contributes to cell death.• This finding provides a mechanism-based rationale for the study of proteasome inhibitors in FLT3-ITD-mutant acute myeloid leukemia.Internal tandem duplication of the Fms-like tyrosine kinase-3 receptor (FLT3) internal tandem duplication (ITD) is found in 30% of acute myeloid leukemia (AML) and is associated with a poor outcome. In addition to tyrosine kinase inhibitors, therapeutic strategies that modulate the expression of FLT3-ITD are also promising. We show that AML samples bearing FLT3-ITD mutations are more sensitive to proteasome inhibitors than wild-type samples and this sensitivity is strongly correlated with a higher FLT3-ITD allelic burden. Using pharmacologic inhibitors of autophagy, specific downregulation of key autophagy proteins including Vps34, autophagy gene (Atg)5, Atg12, Atg13, biochemical, and microscopy studies, we demonstrated that proteasome inhibitors induced cytotoxic autophagy in AML cells. FLT3-ITD molecules were detectable within autophagosomes after bortezomib treatment indicating that autophagy induction was responsible for the early degradation of FLT3-ITD, which preceded the inhibition of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK), PI3K/AKT, and STAT5 pathways, and subsequent activation of cell death. Moreover, proteasome inhibitors overcome resistance to quizartinib induced by mutations in the kinase domain of FLT3, suggesting that these compounds may prevent the emergence of mutant clones arising from tyrosine kinase inhibitor treatments. In xenograft mice models, bortezomib stimulated the conversion of LC3-I to LC3-II, indicating induction of autophagy in vivo, downregulated FLT3-ITD protein expression and improved overall survival. Therefore, selecting patients according to FLT3-ITD mutations could be a new way to detect a significant clinical activity of proteasome inhibitors in AML patients. (Blood. 2016;127(7):882-892)

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“…Endosomal damage by CPP was performed essentially as described before (45). Briefly, cells were plated on poly-D-lysine-treated coverslips.…”

Section: Beclinmentioning

confidence: 99%

Galectin-3 directs antimicrobial guanylate binding proteins to vacuoles furnished with bacterial secretion systems

Feeley

Pilla-Moffett

Zwack

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

127

155

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Many invasive bacteria establish pathogen-containing vacuoles (PVs) as intracellular niches for microbial growth. Immunity to these infections is dependent on the ability of host cells to recognize PVs as targets for host defense. The delivery of several host defense proteins to PVs is controlled by IFN-inducible guanylate binding proteins (GBPs), which themselves dock to PVs through poorly characterized mechanisms. Here, we demonstrate that GBPs detect the presence of bacterial protein secretion systems as “patterns of pathogenesis” associated with PVs. We report that the delivery of GBP2 to Legionella-containing vacuoles is dependent on the bacterial Dot/Icm secretion system, whereas the delivery of GBP2 to Yersinia-containing vacuoles (YCVs) requires hypersecretion of Yersinia translocon proteins. We show that the presence of bacterial secretion systems directs cytosolic carbohydrate-binding protein Galectin-3 to PVs and that the delivery of GBP1 and GBP2 to Legionella-containing vacuoles or YCVs is substantially diminished in Galectin-3–deficient cells. Our results illustrate that insertion of bacterial secretion systems into PV membranes stimulates Galectin-3–dependent recruitment of antimicrobial GBPs to PVs as part of a coordinated host defense program.

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Autophagy Induced by Calcium Phosphate Precipitates Targets Damaged Endosomes

Cited by 70 publications

References 40 publications

Secretory autophagy

Secretory autophagy

Proteasome inhibitors induce FLT3-ITD degradation through autophagy in AML cells

Galectin-3 directs antimicrobial guanylate binding proteins to vacuoles furnished with bacterial secretion systems

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