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Novel azetidine-based Stat3 inhibitors induce misfolded protein response, endoplasmic reticulum stress and mitophagy, and inhibit breast tumor growth in vivo

ABSTRACT: Novel azetidine-based Stat3 inhibitors induce misfolded protein response, endoplasmic reticulum stress and mitophagy, and inhibit breast tumor growth in vivo

PROVIDER: PRJNA746594 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR15142000.fastq.gz	Fastqsanger.gz
	SRR15142001.fastq.gz	Fastqsanger.gz
	SRR15142002.fastq.gz	Fastqsanger.gz
	SRR15142003.fastq.gz	Fastqsanger.gz
	SRR15142004.fastq.gz	Fastqsanger.gz

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The mechanism to dispose of misfolded proteins in the endoplasmic reticulum of adipocytes

Project description:Endoplasmic reticulum (ER)-associated degradation (ERAD) and ER-phagy are two principal degradative mechanisms in the ER; however, the crosstalk between these two pathways and its physiological significance remain unexplored. Here we report that SEL1L-HRD1 ERAD limits autophagy and that, when ERAD is impaired, the ER becomes fragmented containing misfolded ER proteins or aggregates, which are subsequently cleared by autophagy. When both are compromised, ER fragments containing misfolded proteins spatially coalesce into a distinct architecture termed Coalescence of ER Fragments (CERFs), consisted of lipoprotein lipase (LPL) and ER chaperones such as BiP. CERFs enlarge and become increasingly insoluble with age. Finally, we reconstitute the CERFs through LPL and BiP phase separation in vitro, a process controlled by both redox environment and C-terminal tryptophan loop of LPL. Hence, our findings demonstrate a profound cellular adaptation capability and plasticity, centered around SEL1L-HRD1 ERAD, in dealing with misfolded proteins or protein aggregates in the ER.

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IRE1alpha is an endogenous substrate of endoplasmic reticulum-associated degradation

Project description:Endoplasmic reticulum-associated degradation (ERAD) represents a principle quality control (QC) mechanism to clear misfolded proteins in the ER; however, its physiological significance and the nature of endogenous ERAD substrates remain largely unknown. Here we discover that IRE1alpha, the sensor of unfolded protein response (UPR), is a bona fide substrate of the Sel1L-Hrd1 ERAD complex. Mechanistically, ERAD-mediated IRE1alpha degradation occurs in a Bip-dependent manner under basal conditions and is attenuated in response to ER stress. Both intramembrane hydrophilic residues of IRE1alpha and lectin protein OS9 are required for IRE1alpha degradation. ERAD deficiency causes IRE1alpha protein stabilization, accumulation and mild activation both in vitro and in vivo, leading to cellular hypersensitivity to ER stress and inflammation. Furthermore, though enterocyte-specific Sel1L-knockout mice (Sel1LÎ?IEC) are viable and appear normal, they are more susceptible to experimental colitis in an IRE1alpha-dependent but CHOP-independent manner. Collectively, these results demonstrate that Sel1L-Hrd1 ERAD serves a distinct, essential function in restraint of IRE1alpha signaling in vivo by managing its protein turnover. Colon epithelium of wild type and enterocyte-specific Sel1L knockout mice were subjected to gene expression analysis.

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Project description:In eukaryotes, up to one-third of cellular proteins are targeted to the endoplasmic reticulum, where they undergo folding, processing, sorting and trafficking to subsequent endomembrane compartments. Targeting to the endoplasmic reticulum has been shown to occur co-translationally by the signal recognition particle (SRP) pathway or post-translationally by the mammalian transmembrane recognition complex of 40 kDa (TRC40) and homologous yeast guided entry of tail-anchored proteins (GET) pathways. Despite the range of proteins that can be catered for by these two pathways, many proteins are still known to be independent of both SRP and GET, so there seems to be a critical need for an additional dedicated pathway for endoplasmic reticulum relay. We set out to uncover additional targeting proteins using unbiased high-content screening approaches. To this end, we performed a systematic visual screen using the yeast Saccharomyces cerevisiae, and uncovered three uncharacterized proteins whose loss affected targeting. We suggest that these proteins work together and demonstrate that they function in parallel with SRP and GET to target a broad range of substrates to the endoplasmic reticulum. The three proteins, which we name Snd1, Snd2 and Snd3 (for SRP-independent targeting), can synthetically compensate for the loss of both the SRP and GET pathways, and act as a backup targeting system. This explains why it has previously been difficult to demonstrate complete loss of targeting for some substrates. Our discovery thus puts in place an essential piece of the endoplasmic reticulum targeting puzzle, highlighting how the targeting apparatus of the eukaryotic cell is robust, interlinked and flexible.

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IRE1alpha is an endogenous substrate of endoplasmic reticulum-associated degradation

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