bims-ershed 2022-09-04 papers

Issue of 2022‒09‒04
four papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital

Oncoimmunology. 2022 ;11(1): 2116844

IRE1α overexpression in malignant cells limits tumor progression by inducing an anti-cancer immune response.

Adriana Martinez-Turtos, Rachel Paul, Manuel Grima-Reyes, Hussein Issaoui, Adrien Krug, Rana Mhaidly, Jozef P Bossowski, Johanna Chiche, Sandrine Marchetti, Els Verhoeyen, Eric Chevet, Jean-Ehrland Ricci.

IRE1α is one of the three ER transmembrane transducers of the Unfolded Protein Response (UPR) activated under endoplasmic reticulum (ER) stress. IRE1α activation has a dual role in cancer as it may be either pro- or anti-tumoral depending on the studied models. Here, we describe the discovery that exogenous expression of IRE1α, resulting in IRE1α auto-activation, did not affect cancer cell proliferation in vitro but resulted in a tumor-suppressive phenotype in syngeneic immunocompetent mice. We found that exogenous expression of IRE1α in murine colorectal and Lewis lung carcinoma cells impaired tumor growth when syngeneic tumor cells were subcutaneously implanted in immunocompetent mice but not in immunodeficient mice. Mechanistically, the in vivo tumor-suppressive effect of overexpressing IRE1α in tumor cells was associated with IRE1α RNAse activity driving both XBP1 mRNA splicing and regulated IRE1-dependent decay of RNA (RIDD). We showed that the tumor-suppressive phenotype upon IRE1α overexpression was characterized by the induction of apoptosis in tumor cells along with an enhanced adaptive anti-cancer immunosurveillance. Hence, our work indicates that IRE1α overexpression and/or activation in tumor cells can limit tumor growth in immunocompetent mice. This finding might point toward the need of adjusting the use of IRE1α inhibitors in cancer treatments based on the predominant outcome of the RNAse activity of IRE1α.

Keywords: Cancer; IRE1α; RIDD; UPR; XBP1s; anti-cancer immunosurveillance; apoptosis

DOI: https://doi.org/10.1080/2162402X.2022.2116844

Toxicol In Vitro. 2022 Aug 24. pii: S0887-2333(22)00157-6. [Epub ahead of print]85 105459

Fatty acid palmitate suppresses FoxO1 expression via PERK and IRE1 unfolded protein response in C2C12 myotubes.

Boya Zhang, Ruijiao Zhu, Xiaotong Sun, Qian Guo, Yao Zhang, Nanxi Zhang, Yuri Oh, Lei Fan, Changlin Wang, Ning Gu.

Forkhead Box O1 (FoxO1) is a transcription factor with a unique fork head domain that indirectly participates in a variety of physiological processes and plays an important role in type 2 diabetes. Palmitate as the most abundant free fatty acid, accounting for 28-32% of total free fatty acids in human plasma. There is a direct relationship between palmitate and insulin resistance-induced type 2 diabetes. In addition, palmitate can activate the unfolded protein response signaling pathway induced by endoplasmic reticulum (ER) stress. This study aimed to investigate the response of FoxO1 to palmitate and the relationship with ER stress in C2C12 myotubes. Treatment of palmitate or tunicamycin promoted ER stress-related genes expression but suppressed FoxO1 expression, while 4-phenylbutyrate presented the opposite activity in palmitate-pretreated C2C12 myotubes, indicating that ER stress might be closely associated with FoxO1 expression. Moreover, palmitate-suppressed FoxO1 expression was reversed in C2C12 cells when the PERK and IRE-1 signaling pathway was inhibited by treatment with GSK2656157 or 4μ8C. However, no differences were observed when the ATF6 signaling pathway was suppressed by knockout of the ATF6 gene. These findings suggest that palmitate suppressed FoxO1 expression via the PERK and IRE1 signaling pathways.

Keywords: ER stress; FoxO1; IRE1; PERK; Palmitate

DOI: https://doi.org/10.1016/j.tiv.2022.105459

Front Pharmacol. 2022 ;13 940629

Melatonin promotes sirtuin 1 expression and inhibits IRE1α-XBP1S-CHOP to reduce endoplasmic reticulum stress-mediated apoptosis in chondrocytes.

Kunpeng Qin, Hao Tang, Yi Ren, Di Yang, Yetian Li, Wei Huang, Yunfeng Wu, Zongsheng Yin.

Osteoarthritis (OA) is the most common chronic disease characterized by a loss of chondrocytes and the degeneration of cartilage. Inflammation plays an important role in the pathogenesis and progression of OA via the activation of the endoplasmic reticulum (ER) stress signaling pathway. In this study, we stimulated human primary chondrocytes with lipopolysaccharide (LPS) to reduce cell viability and induce chondrocyte apoptosis. LPS-stimulated human primary chondrocytes induced ER stress and significantly upregulated the ER chaperone glucose-regulated protein 78 (GRP78) and increased the expression level of C/EBP-homologous protein (CHOP), a key mediator of ER stress--induced apoptosis. Interestingly, melatonin treatment attenuated ER stress-mediated chondrocyte apoptosis. Melatonin inhibited the expression of cleaved caspase-3, cleaved caspase-10, Bax, CHOP, GRP78, cleaved caspase-4, phospho-inositol-requiring enzyme 1α (P-IRE1α), and spliced X-box-binding protein 1 (XBP1S). In an anterior cruciate ligament transection mouse model of OA, melatonin (50 and 150 mg/kg) dose-dependently relieved joint cartilage degeneration and inhibitied of chondrocyte apoptosis. Immunohistochemical analysis indicated that melatonin could promote SIRT1 the expression and inhibit CHOP and cleaved caspase-3 expression in OA mice. In conclusion, our findings demonstrate for the first time that melatonin inhibits the IRE1α-XBP1S-CHOP signaling pathway by promoting the expression of SIRT1 in LPS-treated human chondrocytes and delaying OA progression in vivo.

Keywords: IRE1α--XBP1S--CHOP; apoptosis; endoplasmic reticulum stress; melatonin; osteoarthritis

DOI: https://doi.org/10.3389/fphar.2022.940629

Mol Biol Cell. 2022 Aug 31. mbcE22070281

Regulation of Blos1 by IRE1 prevents the accumulation of Huntingtin protein aggregates.

Donghwi Bae, Rachel Elizabeth Jones, Katherine M Piscopo, Mitali Tyagi, Jason D Shepherd, Julie Hollien.

Huntington's disease is characterized by accumulation of the aggregation-prone mutant Huntingtin (mHTT) protein. Here, we show that expression of exon 1 of mHTT in mouse cultured cells activates IRE1, the transmembrane sensor of stress in the endoplasmic reticulum, leading to degradation of the Blos1 mRNA and repositioning of lysosomes and late endosomes toward the microtubule organizing center. Overriding Blos1 degradation results in excessive accumulation of mHTT aggregates in both cultured cells and primary neurons. Although mHTT is degraded by macroautophagy when highly expressed, we show that prior to the formation of large aggregates, mHTT is degraded via an ESCRT-dependent, macroautophagy-independent pathway consistent with endosomal microautophagy. This pathway is enhanced by Blos1 degradation and appears to protect cells from a toxic, less aggregated form of mHTT.

DOI: https://doi.org/10.1091/mbc.E22-07-0281