bims-unfpre 2019-06-09 papers

Issue of 2019–06–09
three papers selected by
Susan Logue, University of Manitoba

J Biol Chem. 2019 Jun 05. pii: jbc.RA118.003311. [Epub ahead of print]

An integrated PKD1-dependent signaling network amplifies IRE1 pro-survival signaling.

Shiyong Wu, Shumin Ma, Xueliang Yin, Ping Yi, Jianfeng Liu.

Following the accumulation of improperly folded proteins in the endoplasmic reticulum (ER), a condition known as ER stress in this compartment triggers an adaptive signaling pathway referred to as the unfolded protein response (UPR). The UPR aims at restoring ER homeostasis; if the ER stress cannot be resolved, apoptosis is triggered. However, the mechanisms responsible for regulating the balance between cell life and death decisions that occur after exposure to ER stress remain unclear. Protein kinase D1 (PKD1) has been reported to initiate protective signaling against oxidative stress or ischemia, two conditions that impinge on the induction of ER stress. In addition, the high levels of expression of PKD1, observed in highly proliferative cancers and tumors with poor prognosis, contribute to enhanced resistance to chemotherapy. In this study, we show that the ER stress inducers tunicamycin and thapsigargin lead to the activation of PKD1 in human prostate cancer PC-3 cells and in hepatoma HepG2 cells through a PKCδ-dependent mechanism. Moreover, our data indicate that PKD1 is required for the stabilization of inositol-requiring enzyme 1 (IRE1) and the subsequent regulation of its activity. PKD1 activation contributes to the phosphorylation of MAP kinase phosphatase 1, resulting in decreased IRE1-mediated c-Jun N-terminal kinase activation. This study unveils the existence of a novel PKD1-dependent pro-survival mechanism that is activated upon ER stress and selectively enhances IRE1 pro-survival signaling.

Keywords: IRE1; MKP1; c-Jun N-terminal kinase (JNK); cell death; endoplasmic reticulum stress (ER stress); protein kinase D (PKD); signal transduction

DOI: https://doi.org/10.1074/jbc.RA118.003311

J Biol Chem. 2019 Jun 06. pii: jbc.RA119.007813. [Epub ahead of print]

Deficiency in the membrane protein Tmbim3a/Grinaa initiates cold-induced ER stress and cell death by activating an intrinsic apoptotic pathway in zebrafish.

Kai Chen, Xixi Li, Guili Song, Tong Zhou, Yong Long, Qing Li, Shan Zhong, Zongbin Cui.

Most members of the family of proteins containing a transmembrane BAX inhibitor motif (TMBIM) have anti-apoptotic activity, but their in vivo functions and intracellular mechanisms remain obscure. Here, we report that zebrafish Tmbim3a/Grinaa functions in the prevention of cold-induced endoplasmic reticulum (ER) stress and apoptosis. Using a gene-trapping approach, we obtained a mutant zebrafish line in which the expression of the tmbim3a/grinaa gene is disrupted by a Tol2 transposon insertion. Homozygous tmbim3a/grinaa mutant larvae exhibited time-dependently increased mortality and apoptosis under cold exposure (at 16ºC). Mechanistically, using immunofluorescence, fluorescence-based assessments of intracellular/mitochondrial Ca²+ levels, mitochondrial membrane potential measurements, and Ca²+-ATPase assays, we found that cold exposure suppresses sarcoplasmic/ER Ca²+-ATPase (SERCA) activity and induces the unfolded protein response (UPR) and ER stress. We also found that the cold-induced ER stress is increased in homozygous tmbim3a/grinaa mutant embryos. The cold-stress hyper-sensitivity of the tmbim3a/grinaa mutants was tightly associated with disrupted intracellular Ca²+ homeostasis, followed by mitochondrial Ca²+ overload and cytochrome c release, leading to the activation of caspase 9- and caspase 3-mediated intrinsic apoptotic pathways. Treatment of zebrafish larvae with the intracellular Ca²+ chelator BAPTA-AM or with 2-APB, an inhibitor of the calcium-releasing protein IP3 receptor (IP3R), alleviated cold-induced cell death. Together, these findings unveil a key role of Tmbim3a/Grinaa in relieving cold-induced ER stress and in protecting cells against caspase 9- and 3-mediated apoptosis during zebrafish development.

Keywords: Apoptosis; Calcium homeostasis; Cold exposure; Grinaa; apoptosis; calcium intracellular release; endoplasmic reticulum stress (ER stress); endoplasmic reticulum stress; Calcium homeostasis; stress response; zebrafish

DOI: https://doi.org/10.1074/jbc.RA119.007813

J Immunol. 2019 Jun 05. pii: ji1801546. [Epub ahead of print]

Sec62 Suppresses Foot-and-Mouth Disease Virus Proliferation by Promotion of IRE1α-RIG-I Antiviral Signaling.

Shichong Han, Lejiao Mao, Ying Liao, Shiqi Sun, Zhihui Zhang, Yaxia Mo, Haiyun Liu, Xiaoying Zhi, Shunmei Lin, Ho Seong Seo, Huichen Guo.

Foot-and-mouth disease virus (FMDV) is highly infectious and causes a major plague in animal farming. Unfolded protein response is one of the major cellular responses to pathogenic infections, which performs a crucial role in cell survival, apoptosis, and antiviral innate immune response. In this study, we showed that FMDV infection activated two unfolded protein response branches (PERK-eIF2α and ATF6 signaling) in both baby hamster kidney cells (BHK-21) and porcine kidney (PK-15) cells, whereas it suppressed the IRE1α-XBP1 signaling by decreasing IRE1α level. Further study revealed IRE1α signaling as an important antiviral innate immune mechanism against FMDV. Sec62, the transport protein, was greatly decreased at the late stages of FMDV infection. By overexpression and knockdown study, we also found that the expression of Sec62 was positively involved in the levels of IRE1α and RIG-I and subsequent activation of downstream antiviral signaling pathways in FMDV-infected PK-15 cells. Taken together, our study demonstrates that Sec62 is an important antiviral factor that upregulates IRE1α-RIG-I-dependent antiviral innate immune responses, and FMDV evades antiviral host defense mechanism by downregulating Sec62-IRE1α/RIG-I.

DOI: https://doi.org/10.4049/jimmunol.1801546