PERK activation by SB202190 ameliorates amyloidogenesis via the TFEB-induced autophagy-lysosomal pathway

Do, Mihyang; Park, Jeong-Min; Chen, Yubing; Rah, So-Young; Nghiem, Thu-Hang Thi; Gong, Jeong Heon; Ju, Seong‐A; Kim, Byung-Sam; Yu, Rina; Park, Jeong Woo; Ryter, Stefan W.; Surh, Young‐Joon; Kim, Uh-Hyun; Joe, Yeonsoo; Chung, Hun Taeg

doi:10.18632/aging.203899

Cited by 7 publications

(3 citation statements)

References 44 publications

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“…Interestingly, SB202190 was shown to induce TFE3/TFEB activation and regulate autophagy and lysosome biogenesis independent of p38 inhibition (Yang et al, 2020). Recent studies indicate that the effect of SB202190 on TFEB nuclear localisation is mediated by p38-independent EIF2AK3/PERK activation (Do et al, 2022). Unlike the micron-scale vacuole formation, these effects on TFEB and PERK activation were not reported to be cell-type specific.…”

Section: Discussionmentioning

confidence: 99%

Kinase inhibitor-induced cell-type specific vacuole formation in the absence of canonical ATG5-dependent autophagy

Jose,

Sharma,

Insan

et al. 2023

Preprint

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Pyridinyl imidazole class p38 MAPKα/β (MAPK14/MAPK11) inhibitors including SB202190 have been shown to induce a cell-type specific defective autophagy response resulting in micron-scale vacuole formation and autophagy-dependent death. We had earlier shown that this is an off-target effect of SB202190. Here we provide evidence that the cell-type specific vacuole formation is independent of canonical autophagy pathway. While SB202190 seems to interfere with autophagic flux in many cell lines parallel to vacuolation, autophagy-deficient DU-145 cells and CRISPR/Cas9 gene-editedATG5knockout A549 cells also undergo vacuolation upon SB202190 treatment. Further analyses identified the late-endosomal GTPase RAB7 as a marker for the SB202190-induced micron-scale vacuoles. A screen for modulators of SB202190-induced vacuolation revealed molecules including multi-kinase inhibitor Sorafenib as inhibitor of vacuolation. Moreover VE-821, an ATR kinase inhibitor was found to phenocopy the cell-type specific vacuolation response of SB202190. To identify the factors determining the cell-type specificity of the vacuolation response induced by SB-compounds and VE-821, we compared the transcriptomics data from vacuole forming and non-vacuole forming cancer cell lines and identified a gene expression signature which may define sensitivity of cancer cells to these small-molecule kinase inhibitors. Further analyses using the small molecule tools and the gene signature discovered here, could reveal novel mechanisms regulating this interesting phenotype relevant to anti-cancer therapy.

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Section: Discussionmentioning

confidence: 99%

Kinase inhibitor-induced cell-type specific vacuole formation in the absence of canonical ATG5-dependent autophagy

Jose,

Sharma,

Insan

et al. 2023

Preprint

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“…[29,39] Consistently, in neuroblastoma cells, EIF2AK3 activated Ca 2+ and calcineurin which promoted TFEB nuclear translocation. [42] Carbon monoxide increased mitophagy through TFEB activation by EIF2AK3-increased intracellular Ca 2+ and activity of calcineurin. [43] Thus, our results suggested that SiNP-induced TFEB activation might depend on EIF2AK3-Ca 2+ -calcineurin axis.…”

Section: Discussionmentioning

confidence: 99%

Silica Nanoparticles Trigger Chaperone HSPB8‐Assisted Selective Autophagy via TFEB Activation in Hepatocytes

Zhu

Zhang

Fan

et al. 2022

Small

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The total market volume of SiNPs ranked second among manufactured nanoparticles in 2017. [2] This large-scale production and widespread application make SiNPs more of a risk to human health and the environment. Numerous studies have shown that SiNPs cause varying degrees of damage to the cardiovascular system, the lungs, the liver, and the reproductive system. [3][4][5][6][7] As a major metabolic clearance organ, the liver is the main target of SiNP toxicity. SiNPs can be retained in the liver for up to 60 days after intravenous administration in rats [8] and can cause hepatocyte steatosis, fibrosis, granuloma, and other lesions. [9,10] Therefore, it is urgent to explore the biological effects of SiNPs and underlying mechanisms of hepatotoxicity.Autophagy is a highly conserved degradative process that maintains cellular homeostasis by removing misfolded proteins and damaged organelles via the lysosome. [11] There are three types of autophagy: microautophagy, chaperonemediated autophagy (CMA), and macroautophagy. Both microautophagy and CMA exclusively depend on degradation by the lysosome and do not involve autophagosomes. Macroautophagy/autophagy is the most extensively studied pathway and consists of multiple sequential steps: initiation, elongation, maturation, fusion, and degradation. [12] In addition to non-selective, "in bulk" autophagy can occur in selective manners and be initiated by mitochondria, peroxisomes, nuclei, ribosomes, or lipid droplets (LDs). [13] Furthermore, chaperone-assisted selective autophagy (CASA) is a specialized form of macroautophagy whereby substrate proteins are ubiquitinated and targeted to lysosomal degradation by chaperone and cochaperone proteins. [14] The substrate proteins in CASA do not possess a KFERQ motif for heat shock cognate protein 70 (HSC70) recognition, in which it differs from CMA. In CASA, the cargo proteins are recognized by the CASA complex, which comprises the chaperones HSC70 and heat shock protein family B (small) member 8 (HSPB8) coupled by the cochaperone BAG3. [14] Autophagy is the predominant biological process triggered by nanoparticles. Many nanoparticles have been reported to induce autophagy, such as iron oxide nanoparticles, [15] gold nanoparticles, [16] CoCrMo nanoparticles [17] and silica nanoparticles (SiNPs). [18][19][20] Different Silica nanoparticles (SiNPs) are one of the most common inorganic nanomaterials. Autophagy is the predominant biological response to nanoparticles and transcription factor EB (TFEB) is a master regulator of the autophagylysosome pathway. Previous studies show that SiNPs induce autophagosome accumulation, yet the precise underlying mechanisms remain uncertain. The present study investigates the role of TFEB during SiNP-induced autophagy. SiNP-induced TFEB nuclear translocation is verified using immunofluorescence and western blot assay. The regulation of TFEB is proved to be via EIF2AK3 pathway. A TFEB knockout (KO) cell line is constructed to validate the TFEB involvement in SiNP-induced autophagy. The transcriptomes ...

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“…As lysosomal acidity increases in DCs, the efficiency of cross-presentation wanes due to the premature state of phagosomes. In particular, p38 likely acts as a negative regulator of TFEB-mediated lysosomal biogenesis, especially in microglia ( 65 – 67 ). Hence, careful modulation of lysosomal activity mediated by p38-TFEB signaling axis is also likely critical in determining the fate of an internalized antigen and in regulating the balance between the two exogenous antigen-presenting pathways in DCs.…”

Section: Molecular Mechanisms Of Dendritic Cell Cross-presentationmentioning

confidence: 99%

Vaccine adjuvants to engage the cross-presentation pathway

Lee

Suresh

2022

Front. Immunol.

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Adjuvants are indispensable components of vaccines for stimulating optimal immune responses to non-replicating, inactivated and subunit antigens. Eliciting balanced humoral and T cell-mediated immunity is paramount to defend against diseases caused by complex intracellular pathogens, such as tuberculosis, malaria, and AIDS. However, currently used vaccines elicit strong antibody responses, but poorly stimulate CD8 cytotoxic T lymphocyte (CTL) responses. To elicit potent CTL memory, vaccines need to engage the cross-presentation pathway, and this requirement has been a crucial bottleneck in the development of subunit vaccines that engender effective T cell immunity. In this review, we focus on recent insights into DC cross-presentation and the extent to which clinically relevant vaccine adjuvants, such as aluminum-based nanoparticles, water-in oil emulsion (MF59) adjuvants, saponin-based adjuvants, and Toll-like receptor (TLR) ligands modulate DC cross-presentation efficiency. Further, we discuss the feasibility of using carbomer-based adjuvants as next generation of adjuvant platforms to elicit balanced antibody- and T-cell based immunity. Understanding of the molecular mechanism of DC cross-presentation and the mode of action of adjuvants will pave the way for rational design of vaccines for infectious diseases and cancer that require balanced antibody- and T cell-based immunity.

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PERK activation by SB202190 ameliorates amyloidogenesis via the TFEB-induced autophagy-lysosomal pathway

Cited by 7 publications

References 44 publications

Kinase inhibitor-induced cell-type specific vacuole formation in the absence of canonical ATG5-dependent autophagy

Kinase inhibitor-induced cell-type specific vacuole formation in the absence of canonical ATG5-dependent autophagy

Silica Nanoparticles Trigger Chaperone HSPB8‐Assisted Selective Autophagy via TFEB Activation in Hepatocytes

Vaccine adjuvants to engage the cross-presentation pathway

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