bims-ershed 2022-01-02 papers

Plant Signal Behav. 2021 Dec 30. 2018857

The interplay of GTP-binding protein AGB1 with ER stress sensors IRE1a and IRE1b modulates Arabidopsis unfolded protein response and bacterial immunity.

Taiaba Afrin, Caitlin N Costello, Amber N Monella, Camilla J Kørner, Karolina M Pajerowska-Mukhtar.

In eukaryotic cells, the accumulation of unfolded or misfolded proteins in the endoplasmic reticulum (ER) results in ER stress that induces a cascade of reactions called the unfolded protein response (UPR). In Arabidopsis, the most conserved UPR sensor, Inositol-requiring enzyme 1 (IRE1), responds to both abiotic- and biotic-induced ER stress. Guanine nucleotide-binding proteins (G proteins) constitute another universal and conserved family of signal transducers that have been extensively investigated due to their ubiquitous presence and diverse nature of action. Arabidopsis GTP-binding protein β1 (AGB1) is the only G-protein β-subunit encoded by the Arabidopsis genome that is involved in numerous signaling pathways. Mounting evidence suggests the existence of a crosstalk between IRE1 and G protein signaling during ER stress. AGB1 has previously been shown to control a distinct UPR pathway independently of IRE1 when treated with an ER stress inducer tunicamycin. Our results obtained with combinatorial knockout mutants support the hypothesis that both IRE1 and AGB1 synergistically contribute to ER stress responses chemically induced by dithiothreitol (DTT) as well as to the immune responses against a phytopathogenic bacterium Pseudomonas syringae pv. tomato strain DC3000. Our study highlights the crosstalk between the plant UPR transducers under abiotic and biotic stress.

Keywords: Arabidopsis thaliana; GTP-binding Protein B1; Inositol-Requiring Enzyme 1; Pseudomonas syringae pv. tomato DC3000; Unfolded Protein Response

DOI: https://doi.org/10.1080/15592324.2021.2018857

J Biol Chem. 2021 Dec 22. pii: S0021-9258(21)01342-9. [Epub ahead of print] 101532

The ER stress sensor inositol-requiring enzyme 1α in Kupffer cells promotes hepatic ischemia-reperfusion injury.

Jie Cai, Xiaoge Zhang, Peng Chen, Yang Li, Songzi Liu, Qian Liu, Hanyong Zhang, Zhuyin Wu, Ke Song, Jianmiao Liu, Bo Shan, Yong Liu.

Hepatic ischemia/reperfusion (I/R) injury is an inflammation-mediated process arising from ischemia/reperfusion-elicited stress in multiple cell types, causing liver damage during surgical procedures and often resulting in liver failure. Endoplasmic reticulum (ER) stress triggers the activation of the unfolded protein response (UPR) and is implicated in tissue injuries, including hepatic I/R injury. However, the cellular mechanism that links the UPR signaling to local inflammatory responses during hepatic I/R injury remains largely obscure. Here, we report that IRE1α, a critical ER-resident transmembrane signal transducer of the UPR, plays an important role in promoting Kupffer cell-mediated liver inflammation and hepatic I/R injury. Utilizing a mouse model in which IRE1α is specifically ablated in myeloid cells, we found that abrogation of IRE1α markedly attenuated necrosis and cell death in the liver, accompanied by reduced neutrophil infiltration and liver inflammation following hepatic I/R injury. Mechanistic investigations in mice as well as in primary Kupffer cells revealed that loss of IRE1α in Kupffer cells not only blunted the activation of the NLRP3 inflammasome and IL-1β production, but also suppressed the expression of the inducible nitric oxide synthase (iNos) and pro-inflammatory cytokines. Moreover, pharmacological inhibition of IRE1α's RNase activity was able to attenuate inflammasome activation and iNos expression in Kupffer cells, leading to alleviation of hepatic I/R injury in mice. Collectively, these results demonstrate that Kupffer cell IRE1α mediates local inflammatory damage during hepatic I/R injury. Our findings suggest that IRE1α RNase activity may serve as a promising target for therapeutic treatment of ischemia/reperfusion-associated liver inflammation and dysfunction.

Keywords: ER stress; Hepatic ischemia/reperfusion injury; IRE1α; Inflammation; Kupffer cells

DOI: https://doi.org/10.1016/j.jbc.2021.101532

Cell Rep. 2021 Dec 28. pii: S2211-1247(21)01674-0. [Epub ahead of print]37(13): 110174

USP19 exacerbates lipogenesis and colorectal carcinogenesis by stabilizing ME1.

Yahui Zhu, Li Gu, Xi Lin, Xinyi Zhou, Bingjun Lu, Cheng Liu, Caoqi Lei, Feng Zhou, Qiu Zhao, Edward V Prochownik, Youjun Li.

Lipogenesis plays a critical role in colorectal carcinogenesis, but precisely how remains unclear. Here, we show that ERK2 phosphorylates ME1 at T103, thereby inhibiting its polyubiquitination and proteasomal degradation and enhancing its interaction with USP19. USP19 antagonizes RNF1-mediated ME1 degradation by deubiquitination, which in turn promotes lipid metabolism and NADPH production and suppresses ROS. Meanwhile, ROS dramatically increases PD-L1 mRNA levels through accelerating expression of the transcription factor NRF2. Increased lipid metabolism is correlated with ERK2 activity and colorectal carcinogenesis in human patients. Therefore, the combination of ERK2 inhibitor and anti-PD-L1 antibody significantly inhibits spontaneous and chemically induced colorectal carcinogenesis. Collectively, the USP19-ME1 axis plays a vital role in colorectal carcinogenesis and may also provide a potential therapeutic target.

Keywords: ME1; PD-L1; USP19; deubiquitination; lipogenesis

DOI: https://doi.org/10.1016/j.celrep.2021.110174