bims-unfpre 2022-07-10 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2022–07–10
nine papers selected by
Susan Logue, University of Manitoba

Neuron-specific translational control shift ensures proteostatic resilience during ER stress.
FKBP11 rewires UPR signaling to promote glucose homeostasis in type 2 diabetes and obesity.
Towards Understanding the Relationship Between ER Stress and Unfolded Protein Response in Amyotrophic Lateral Sclerosis.
Unfolded protein response is involved in the metabolic and apoptotic regulation of oral squamous cell carcinoma.
Transmissible ER stress between macrophages and tumor cells configures tumor microenvironment.
UPR Responsive Genes Manf and Xbp1 in Stroke.
Diabesity? No worries, FKBP11 to the rescue.
Targeting autophagy increases the efficacy of proteasome inhibitor treatment in multiple myeloma by induction of apoptosis and activation of JNK.
Spautin-1 inhibits mitochondrial complex I and leads to suppression of the unfolded protein response and cell survival during glucose starvation.

EMBO J. 2022 Jul 06. e110501

Neuron-specific translational control shift ensures proteostatic resilience during ER stress.

Kimberly Wolzak, Anna Nölle, Margherita Farina, Truus Em Abbink, Marjo S van der Knaap, Matthijs Verhage, Wiep Scheper.

  Proteostasis is essential for cellular survival and particularly important for highly specialised post-mitotic cells such as neurons. Transient reduction in protein synthesis by protein kinase R-like endoplasmic reticulum (ER) kinase (PERK)-mediated phosphorylation of eukaryotic translation initiation factor 2α (p-eIF2α) is a major proteostatic survival response during ER stress. Paradoxically, neurons are remarkably tolerant to PERK dysfunction, which suggests the existence of cell type-specific mechanisms that secure proteostatic stress resilience. Here, we demonstrate that PERK-deficient neurons, unlike other cell types, fully retain the capacity to control translation during ER stress. We observe rescaling of the ATF4 response, while the reduction in protein synthesis is fully retained. We identify two molecular pathways that jointly drive translational control in PERK-deficient neurons. Haem-regulated inhibitor (HRI) mediates p-eIF2α and the ATF4 response and is complemented by the tRNA cleaving RNase angiogenin (ANG) to reduce protein synthesis. Overall, our study elucidates an intricate back-up mechanism to ascertain translational control during ER stress in neurons that provides a mechanistic explanation for the thus far unresolved observation of neuronal resilience to proteostatic stress.

Keywords:  ANG; HRI; PERK; neuron-specific; translational control

DOI:  https://doi.org/10.15252/embj.2021110501
Cell Metab. 2022 Jul 05. pii: S1550-4131(22)00227-3. [Epub ahead of print]34(7): 1004-1022.e8

FKBP11 rewires UPR signaling to promote glucose homeostasis in type 2 diabetes and obesity.

Hilde Herrema, Dongxian Guan, Jae Won Choi, Xudong Feng, Mario Andres Salazar Hernandez, Farhana Faruk, Thomas Auen, Eliza Boudett, Rongya Tao, Hyonho Chun, Umut Ozcan.

  Chronic endoplasmic reticulum (ER) stress and sustained activation of unfolded protein response (UPR) signaling contribute to the development of type 2 diabetes in obesity. UPR signaling is a complex signaling pathway, which is still being explored in many different cellular processes. Here, we demonstrate that FK506-binding protein 11 (FKBP11), which is transcriptionally regulated by XBP1s, is severely reduced in the livers of obese mice. Restoring hepatic FKBP11 expression in obese mice initiates an atypical UPR signaling pathway marked by rewiring of PERK signaling toward NRF2, away from the eIF2α-ATF4 axis of the UPR. This alteration in UPR signaling establishes glucose homeostasis without changing hepatic ER stress, food consumption, or body weight. We conclude that ER stress during obesity can be beneficially rewired to promote glucose homeostasis. These findings may uncover possible new avenues in the development of novel approaches to treat diseases marked by ER stress.

Keywords:  ER stress; FKBP11; NRF2; UPR signaling; glucose intolerance; insulin resistance; obesity; type 2 diabetes

DOI:  https://doi.org/10.1016/j.cmet.2022.06.007
Front Aging Neurosci. 2022 ;14 892518

Towards Understanding the Relationship Between ER Stress and Unfolded Protein Response in Amyotrophic Lateral Sclerosis.

Chenxuan Zhao, Yong Liao, Abdul Rahaman, Vijay Kumar.

  Biological stress due to the aberrant buildup of misfolded/unfolded proteins in the endoplasmic reticulum (ER) is considered a key reason behind many human neurodegenerative diseases. Cells adapted to ER stress through the activation of an integrated signal transduction pathway known as the unfolded protein response (UPR). Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by degeneration of the motor system. It has largely been known that ER stress plays an important role in the pathogenesis of ALS through the dysregulation of proteostasis. Moreover, accumulating evidence indicates that ER stress and UPR are important players in TDP-43 pathology. In this mini-review, the complex interplay between ER stress and the UPR in ALS and TDP-43 pathology will be explored by taking into account the studies from in vitro and in vivo models of ALS. We also discuss therapeutic strategies to control levels of ER stress and UPR signaling components that have contrasting effects on ALS pathogenesis.

Keywords:  ALS; ER stress; TDP-43; UPR; pharmacological modulator

DOI:  https://doi.org/10.3389/fnagi.2022.892518
Pathology. 2022 Jul 02. pii: S0031-3025(22)00176-3. [Epub ahead of print]

Unfolded protein response is involved in the metabolic and apoptotic regulation of oral squamous cell carcinoma.

B Seo, D E Coates, J Lewis, G J Seymour, A M Rich.

  Endoplasmic reticulum (ER) stress and unfolded protein response (UPR) have been shown to be crucial in the pathogenesis and response to treatment in various cancers. However, such response has not been profiled in oral squamous cell carcinoma (OSCC), the most frequent form of cancer in the head and neck region. Cell lines derived from OSCC (SCC4, SCC15 and SCC25) and normal oral mucosa (OKF4, OKF6 and OKP7) were subjected to tunicamycin-induced ER stress (2.5 μg/mL for 24 h) after which the differential regulation of 84 key UPR/ER stress genes were assessed using Quantitative real-time reverse transcription polymerase chain reaction. The expression of the transcription factors SREBP1 and CREB3L3, and the activation of SREBP1, were examined using ELISA and a transcription factor assay. The expression of DDIT3 was immunohistochemically verified in OSCC tissue samples. SREBP1 and CREB3L3 were significantly up-regulated in OSCC with and without tunicamycin-induced ER stress. A significantly higher level of SREBP1 transcriptional activation was observed in OSCC. Apoptosis-associated genes (DDIT3, HTRA4 and HSPA1L) were also significantly up-regulated in OSCC upon ER stress induction. The findings demonstrated the involvement of UPR and ER stress in the pathogenesis of OSCC through the identification of apoptosis-associated genes (DDIT3, HSPA1L and HTRA4) and regulators of metabolism (SREBP1 and CREB3L3) as the key factors differentiating between normal and malignant oral keratinocytes.

Keywords:  CREB3L3; DDIT3; ER stress; OSCC; SREBF1; SREBP1; UPR; apoptosis; heat shock protein; oral cancer

DOI:  https://doi.org/10.1016/j.pathol.2022.04.003
Cell Mol Life Sci. 2022 Jul 07. 79(8): 403

Transmissible ER stress between macrophages and tumor cells configures tumor microenvironment.

Wei Wei, Yazhuo Zhang, Qiaoling Song, Qianyue Zhang, Xiaonan Zhang, Xinning Liu, Zhihua Wu, Xiaohan Xu, Yuting Xu, Yu Yan, Chenyang Zhao, Jinbo Yang.

  Endoplasmic reticulum (ER) stress initiates the unfolded protein response (UPR) and is decisive for tumor cell growth and tumor microenvironment (TME) maintenance. Tumor cells persistently undergo ER stress and could transmit it to the neighboring macrophages and surroundings. Tumor infiltrating macrophages can also adapt to the microenvironment variations to fulfill their highly energy-demanding and biological functions via ER stress. However, whether the different macrophage populations differentially sense ER stress and transmit ER stress to surrounding tumor cells has not yet been elucidated. Here, we aimed to investigate the role of transmissible ER stress, a novel regulator of intercellular communication in the TME. Murine bone marrow-derived macrophage (BMDM) can be polarized toward distinct functional endpoints termed classical (M1) and alternative (M2) activation, and their polarization status has been shown to be tightly correlated with their functional significance. We showed that tumor cells could receive the transmissible ER stress from two differentially polarized macrophage populations with different extent of ER stress activation. The proinflammatory M1-like macrophages respond to ER stress with less extent, however they could transmit more ER stress to tumor cells. Moreover, by analyzing the secreted components of two ER-stressed macrophage populations, we identified certain damage-associated molecular patterns (DAMPs), including S100A8 and S100A9, which are dominantly secreted by M1-like macrophages could lead to significant recipient tumor cells death in synergy with transferred ER stress.

Keywords:  Intratumoral cell communications; MAPK; Macrophage polarization; Secreted molecules; TME editing; Tumor killing effects

DOI:  https://doi.org/10.1007/s00018-022-04413-z
Front Cell Neurosci. 2022 ;16 900725

UPR Responsive Genes Manf and Xbp1 in Stroke.

Helike Lõhelaid, Jenni E Anttila, Hock-Kean Liew, Kuan-Yin Tseng, Jaakko Teppo, Vassilis Stratoulias, Mikko Airavaara.

  Stroke is a devastating medical condition with no treatment to hasten recovery. Its abrupt nature results in cataclysmic changes in the affected tissues. Resident cells fail to cope with the cellular stress resulting in massive cell death, which cannot be endogenously repaired. A potential strategy to improve stroke outcomes is to boost endogenous pro-survival pathways. The unfolded protein response (UPR), an evolutionarily conserved stress response, provides a promising opportunity to ameliorate the survival of stressed cells. Recent studies from us and others have pointed toward mesencephalic astrocyte-derived neurotrophic factor (MANF) being a UPR responsive gene with an active role in maintaining proteostasis. Its pro-survival effects have been demonstrated in several disease models such as diabetes, neurodegeneration, and stroke. MANF has an ER-signal peptide and an ER-retention signal; it is secreted by ER calcium depletion and exits cells upon cell death. Although its functions remain elusive, conducted experiments suggest that the endogenous MANF in the ER lumen and exogenously administered MANF protein have different mechanisms of action. Here, we will revisit recent and older bodies of literature aiming to delineate the expression profile of MANF. We will focus on its neuroprotective roles in regulating neurogenesis and inflammation upon post-stroke administration. At the same time, we will investigate commonalities and differences with another UPR responsive gene, X-box binding protein 1 (XBP1), which has recently been associated with MANF's function. This will be the first systematic comparison of these two UPR responsive genes aiming at revealing previously uncovered associations between them. Overall, understanding the mode of action of these UPR responsive genes could provide novel approaches to promote cell survival.

Keywords:  ARMET; CDNF; ER stress; IRE1; XBP1; mesencephalic astrocyte-derived neurotrophic factor; unfolded protein response

DOI:  https://doi.org/10.3389/fncel.2022.900725
Cell Metab. 2022 Jul 05. pii: S1550-4131(22)00226-1. [Epub ahead of print]34(7): 942-944

Diabesity? No worries, FKBP11 to the rescue.

Michael Karin.

Obesity-induced type 2 diabetes, or diabesity, is associated with ER stress, UPR activation, and insulin resistance through poorly understood mechanisms. Herrema et al. (2022) report that the XBP1 target FKBP11 is repressed in the obese mouse liver and that its re-expression activates a protective UPR pathway that restores insulin sensitivity.

DOI: https://doi.org/10.1016/j.cmet.2022.06.006
BMC Cancer. 2022 Jul 06. 22(1): 735

Targeting autophagy increases the efficacy of proteasome inhibitor treatment in multiple myeloma by induction of apoptosis and activation of JNK.

Azam Salimi, Kema Marlen Schroeder, Mirle Schemionek-Reinders, Margherita Vieri, Saskia Maletzke, Deniz Gezer, Behzad Kharabi Masouleh, Iris Appelmann.

   BACKGROUND: The therapeutic armamentarium in multiple myeloma has been significantly broadened by proteasome inhibitors, highly efficient means in controlling of multiple myeloma. Despite the developments of therapeutic regimen in treatment of multiple myeloma, still the complete remission requires a novel therapeutic strategy with significant difference in outcomes. Proteasome inhibitors induce autophagy and ER stress, both pivotal pathways for protein homeostasis. Recent studies showed that the IRE1α-XBP1 axis of the unfolded protein response (UPR) is up-regulated in multiple myeloma patients. In addition, XBP1 is crucial for the maintenance of viability of acute lymphoblastic leukemia (ALL).
RESULTS: We analyzed the efficacy of targeting IRE1α-XBP1 axis and autophagy in combination with proteasome inhibitor, ixazomib in treatment of multiple myeloma. In this present study, we first show that targeting the IRE1α-XBP1 axis with small molecule inhibitors (STF-083010, A106) together with the ixazomib induces cell cycle arrest with an additive cytotoxic effect in multiple myeloma. Further, we examined the efficacy of autophagy inhibitors (bafilomycin A, BAF and chloroquine, CQ) together with ixazomib in multiple myeloma and observed that this combination treatment synergistically reduced cell viability in multiple myeloma cell lines (viable cells Ixa: 51.8 ± 3.3, Ixa + BAF: 18.3 ± 7.2, Ixa + CQ: 38.4 ± 3.7) and patient-derived multiple myeloma cells (Ixa: 59.6 ± 4.4, Ixa + CQ: 7.0 ± 2.1). We observed, however, that this combined strategy leads to activation of stress-induced c-Jun N-terminal kinase (JNK). Cytotoxicity mediated by combined proteasome and autophagy inhibition was reversed by addition of the specific JNK inhibitor JNK-In-8 (viable cells: Ixa + BAF: 11.6 ± 7.0, Ixa + BAF + JNK-In-8: 30.9 ± 6.1).
CONCLUSION: In this study we showed that combined inhibition of autophagy and the proteasome synergistically induces cell death in multiple myeloma. Hence, we consider the implication of pharmaceutical inhibition of autophagy together with proteasome inhibition and UPR-directed therapy as promising novel in vitro treatment strategy against multiple myeloma.

Keywords:  Autophagy; Jnk; Multiple myeloma; Proteasome inhibition

DOI:  https://doi.org/10.1186/s12885-022-09775-y
Sci Rep. 2022 Jul 07. 12(1): 11533

Spautin-1 inhibits mitochondrial complex I and leads to suppression of the unfolded protein response and cell survival during glucose starvation.

Kazuhiro Kunimasa, Chika Ikeda-Ishikawa, Yuri Tani, Satomi Tsukahara, Junko Sakurai, Yuka Okamoto, Masaru Koido, Shingo Dan, Akihiro Tomida.

The unfolded protein response (UPR) is an adaptive stress response pathway that is essential for cancer cell survival under endoplasmic reticulum stress such as during glucose starvation. In this study, we identified spautin-1, an autophagy inhibitor that suppresses ubiquitin-specific peptidase 10 (USP10) and USP13, as a novel UPR inhibitor under glucose starvation conditions. Spautin-1 prevented the induction of UPR-associated proteins, including glucose-regulated protein 78, activating transcription factor 4, and a splicing variant of x-box-binding protein-1, and showed preferential cytotoxicity in glucose-starved cancer cells. However, USP10 and USP13 silencing and treatment with other autophagy inhibitors failed to result in UPR inhibition and preferential cytotoxicity during glucose starvation. Using transcriptome and chemosensitivity-based COMPARE analyses, we identified a similarity between spautin-1 and mitochondrial complex I inhibitors and found that spautin-1 suppressed the activity of complex I extracted from isolated mitochondria. Our results indicated that spautin-1 may represent an attractive mitochondria-targeted seed compound that inhibits the UPR and cancer cell survival during glucose starvation.

DOI: https://doi.org/10.1038/s41598-022-15673-x