bims-unfpre 2024-08-25 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2024–08–25
eight papers selected by
Susan Logue, University of Manitoba

The unfolded protein response regulates ER exit sites via SNRPB-dependent RNA splicing and contributes to bone development.
The unfolded protein response sensor PERK mediates mechanical stress-induced maturation of focal adhesion complexes in glioblastoma cells.
Targeting PERK and GRP78 in colorectal cancer: Genetic insights and novel therapeutic approaches.
The emerging role of fat-inducing transcript 2 in endoplasmic reticulum proteostasis and lipoprotein biogenesis.
Jumonji histone demethylases are therapeutic targets in small cell lung cancer.
Chimeric peptide-engineered immunostimulant for endoplasmic reticulum targeted photodynamic immunotherapy against metastatic tumor.
SKN-1 Activation During Infection of C. elegans Requires CDC-48 and ER Proteostasis.
Unfolded proteins in the mitochondria activate HRI and inhibit mitochondrial protein translation.

EMBO J. 2024 Aug 19.

The unfolded protein response regulates ER exit sites via SNRPB-dependent RNA splicing and contributes to bone development.

Muhammad Zahoor, Yanchen Dong, Marco Preussner, Veronika Reiterer, Sabrina Shameen Alam, Margot Haun, Utku Horzum, Yannick Frey, Renata Hajdu, Stephan Geley, Valerie Cormier-Daire, Florian Heyd, Loydie A Jerome-Majewska, Hesso Farhan.

  Splicing and endoplasmic reticulum (ER)-proteostasis are two key processes that ultimately regulate the functional proteins that are produced by a cell. However, the extent to which these processes interact remains poorly understood. Here, we identify SNRPB and other components of the Sm-ring, as targets of the unfolded protein response and novel regulators of export from the ER. Mechanistically, The Sm-ring regulates the splicing of components of the ER export machinery, including Sec16A, a component of ER exit sites. Loss of function of SNRPB is causally linked to cerebro-costo-mandibular syndrome (CCMS), a genetic disease characterized by bone defects. We show that heterozygous deletion of SNRPB in mice resulted in bone defects reminiscent of CCMS and that knockdown of SNRPB delays the trafficking of type-I collagen. Silencing SNRPB inhibited osteogenesis in vitro, which could be rescued by overexpression of Sec16A. This rescue indicates that the role of SNRPB in osteogenesis is linked to its effects on ER-export. Finally, we show that SNRPB is a target for the unfolded protein response, which supports a mechanistic link between the spliceosome and ER-proteostasis. Our work highlights components of the Sm-ring as a novel node in the proteostasis network, shedding light on CCMS pathophysiology.

Keywords:  COPII; Endoplasmic Reticulum; Proteostasis; Sec16A; Splicing

DOI:  https://doi.org/10.1038/s44318-024-00208-z
FEBS Lett. 2024 Aug 16.

The unfolded protein response sensor PERK mediates mechanical stress-induced maturation of focal adhesion complexes in glioblastoma cells.

Mohammad Khoonkari, Dong Liang, Marleen Kamperman, Patrick van Rijn, Frank A E Kruyt.

  Stiffening of the brain extracellular matrix (ECM) in glioblastoma promotes tumor progression. Previously, we discovered that protein kinase R (PKR)-like endoplasmic reticulum kinase (PERK) plays a role in glioblastoma stem cell (GSC) adaptation to matrix stiffness through PERK/FLNA-dependent F-actin remodeling. Here, we examined the involvement of PERK in detecting stiffness changes via focal adhesion complex (FAC) formation. Compared to control GSCs, PERK-deficient GSCs show decreased vinculin and tensin expression, while talin and integrin-β1 remain constant. Furthermore, vimentin was also reduced while tubulin increased, and a stiffness-dependent increase of the differentiation marker GFAP expression was absent in PERK-deficient GSCs. In conclusion, our study reveals a novel role for PERK in FAC formation during matrix stiffening, which is likely linked to its regulation of F-actin remodeling.

Keywords:  extracellular matrix; focal adhesion complex; glioblastoma; mechanical stress; unfolded protein response

DOI:  https://doi.org/10.1002/1873-3468.14996
Eur J Pharmacol. 2024 Aug 15. pii: S0014-2999(24)00588-0. [Epub ahead of print]982 176899

Targeting PERK and GRP78 in colorectal cancer: Genetic insights and novel therapeutic approaches.

Sahar Mafi, Mehdi Dehghani, Bahman Khalvati, Hassan Abidi, Marziyeh Ghorbani, Pooya Jalali, Rachel Whichelo, Zahra Salehi, Aleksandra Markowska, Amanda Reyes, Stevan Pecic, Marek J Łos, Saeid Ghavami, Mohsen Nikseresht.

  Colorectal cancer (CRC) ranks among the leading causes of cancer-related deaths worldwide. Enhancing CRC diagnosis and prognosis requires the development of improved biomarkers and therapeutic targets. Emerging evidence suggests that the unfolded protein response (UPR) plays a pivotal role in CRC progression, presenting new opportunities for diagnosis, treatment, and prevention. This study hypothesizes that genetic variants in endoplasmic reticulum (ER) stress response genes influence CRC susceptibility. We examined the frequencies of SNPs in PERK (rs13045) and GRP78/BiP (rs430397) within a South Iranian cohort. We mapped the cellular and molecular features of PERK and GRP78 genes in colorectal cancer, observing their differential expressions in tumor and metastatic tissues. We constructed co-expression and protein-protein interaction networks and performed gene set enrichment analysis, highlighting autophagy as a significant pathway through KEGG. Furthermore, the study included 64 CRC patients and 60 control subjects. DNA extraction and genotyping were conducted using high-resolution melting (HRM) analysis. Significant differences in PERK and GRP78 expressions were observed between CRC tissues and controls. Variations in PERK and GRP78 genotypes were significantly correlated with CRC risk. Utilizing a Multi-Target Directed Ligands approach, a dual PERK/GRP78 inhibitor was designed and subjected to molecular modeling studies. Docking experiments indicated high-affinity binding between the proposed inhibitor and both genes, PERK and GRP78, suggesting a novel therapy for CRC. These findings highlight the importance of understanding genetic backgrounds in different populations to assess CRC risk. Polymorphisms in UPR signaling pathway elements may serve as potential markers for predicting CRC susceptibility, paving the way for personalized therapeutic strategies.

Keywords:  Colorectal cancer; ER stress; Molecular modeling studies; Multi-target directed ligands; Unfolded protein response

DOI:  https://doi.org/10.1016/j.ejphar.2024.176899
Curr Opin Lipidol. 2024 Aug 23.

The emerging role of fat-inducing transcript 2 in endoplasmic reticulum proteostasis and lipoprotein biogenesis.

Jeffrey L Brodsky, Anuradha Iyer, Konstantinos I Fortounas, Edward A Fisher.

PURPOSE OF REVIEW: This review examines the evolving role of the fat-inducing transcript 2 (FIT2) protein in lipid droplet (LD) biology and its broader implications in cellular physiology and disease. With recent advancements in understanding FIT2 function across various model systems, this review provides a timely synthesis of its mechanisms and physiological significance.
RECENT FINDINGS: FIT2, an endoplasmic reticulum (ER)-resident protein, has been established as a critical regulator of LD formation in diverse organisms, from yeast to mammals. It facilitates LD biogenesis by sequestering diacylglycerol (DAG) and potentially influencing ER membrane dynamics. Beyond its role in lipid metabolism, FIT2 intersects with the ER-associated degradation (ERAD), is critical for protein homeostasis, and is linked to the unfolded protein response (UPR). Dysregulation of FIT2 has also been linked to metabolic disorders such as insulin resistance and lipodystrophy, highlighting its clinical relevance.
SUMMARY: Insights into FIT2 function underscore its pivotal role in LD formation and lipid homeostasis. Understanding its involvement in ER proteostasis and very low density lipoprotein biogenesis has broad implications for metabolic diseases and cancer. Therapeutic strategies targeting FIT2 may offer novel approaches to modulate lipid metabolism and mitigate associated pathologies. Further research is needed to elucidate the full spectrum of FIT2's interactions within cellular lipid and protein networks, potentially uncovering new therapeutic avenues for metabolic and ER stress-related disorders.

DOI: https://doi.org/10.1097/MOL.0000000000000943
Oncogene. 2024 Aug 18.

Jumonji histone demethylases are therapeutic targets in small cell lung cancer.

Aiden Nguyen, Clarissa G Nuñez, Tram Anh Tran, Luc Girard, Michael Peyton, Rodrigo Catalan, Cristina Guerena, Kimberley Avila, Benjamin J Drapkin, Raghav Chandra, John D Minna, Elisabeth D Martinez.

Small cell lung cancer (SCLC) is a recalcitrant cancer of neuroendocrine (NE) origin. Changes in therapeutic approaches against SCLC have been lacking over the decades. Here, we use preclinical models to identify a new therapeutic vulnerability in SCLC consisting of the targetable Jumonji lysine demethylase (KDM) family. We show that Jumonji demethylase inhibitors block malignant growth and that etoposide-resistant SCLC cell lines are particularly sensitive to Jumonji inhibition. Mechanistically, small molecule-mediated inhibition of Jumonji KDMs activates endoplasmic reticulum (ER) stress genes, upregulates ER stress signaling, and triggers apoptotic cell death. Furthermore, Jumonji inhibitors decrease protein levels of SCLC NE markers INSM1 and Secretogranin-3 and of driver transcription factors ASCL1 and NEUROD1. Genetic knockdown of KDM4A, a Jumonji demethylase highly expressed in SCLC and a known regulator of ER stress genes, induces ER stress response genes, decreases INSM1, Secretogranin-3, and NEUROD1 and inhibits proliferation of SCLC in vitro and in vivo. Lastly, we demonstrate that two different small molecule Jumonji KDM inhibitors (pan-inhibitor JIB-04 and KDM4 inhibitor SD70) block the growth of SCLC tumor xenografts in vivo. Our study highlights the translational potential of Jumonji KDM inhibitors against SCLC, a clinically feasible approach in light of recently opened clinical trials evaluating this drug class, and establishes KDM4A as a relevant target across SCLC subtypes.

DOI: https://doi.org/10.1038/s41388-024-03125-x
J Control Release. 2024 Aug 20. pii: S0168-3659(24)00552-2. [Epub ahead of print]374 230-241

Chimeric peptide-engineered immunostimulant for endoplasmic reticulum targeted photodynamic immunotherapy against metastatic tumor.

Rongrong Zheng, Ni Yang, Qiuyuan Li, Zuxiao Chen, Chuyu Huang, Linping Zhao, Xin Chen, Shiying Li.

  The combination of therapy-induced immunogenic cell death (ICD) and immune checkpoint blockade can provide a mutually reinforced strategy to reverse the poor immunogenicity and immune escape behavior of tumors. In this work, a chimeric peptide-engineered immunostimulant (ER-PPB) is fabricated for endoplasmic reticulum (ER)-targeted photodynamic immunotherapy against metastatic tumors. Among which, the amphiphilic chimeric peptide (ER-PP) is composed of ER-targeting peptide FFKDEL, hydrophilic PEG8 linker and photosensitizer protoporphyrin IX (PpIX), which could be assembled with a PD-1/PD-L1 blocker (BMS-1) to prepare ER-PPB. After passively targeting at tumor tissues, ER-PPB will selectively accumulate in the ER. Next, the localized PDT of ER-PPB will produce a lot of ROS to destroy the primary tumor cells, while increasing the ER stress to initiate a robust ICD cascade. Moreover, the concomitant delivery of BMS-1 can impede the immune escape of tumor cells through PD-1/PD-L1 blockade, thus synergistically activating the immune system to combat metastatic tumors. In vitro and in vivo results demonstrate the robust immune activation and metastatic tumor inhibition characteristics of ER-PPB, which may offer a promising strategy for spatiotemporally controlled metastatic tumor therapy.

Keywords:  Endoplasmic reticulum stress; Endoplasmic reticulum targeting; Immune checkpoint blockade; Immunogenic cell death; Photodynamic therapy

DOI:  https://doi.org/10.1016/j.jconrel.2024.08.013
Genetics. 2024 Aug 21. pii: iyae131. [Epub ahead of print]

SKN-1 Activation During Infection of C. elegans Requires CDC-48 and ER Proteostasis.

Carolaing Gabaldón, Ozgur Karakuzu, Danielle A Garsin.

  During challenge of Caenorhabditis elegans with human bacterial pathogens such as Pseudomonas aeruginosa and Enterococcus faecalis, the elicited host response can be damaging if not properly controlled. The activation of Nrf (nuclear factor erythroid-related factor)/CNC (Cap-n-collar) transcriptional regulators modulates the response by upregulating genes that neutralize damaging molecules and promote repair processes. Activation of the C. elegans Nrf ortholog, SKN-1, is tightly controlled by a myriad of regulatory mechanisms, but a central feature is an activating phosphorylation accomplished by the p38 mitogen-activated kinase (MAPK) cascade. In this work, loss of CDC-48, an AAA+ ATPase was observed to severely compromise SKN-1 activation on pathogen and we sought to understand the mechanism. CDC-48 is part of the endoplasmic reticulum (ER) - associated degradation (ERAD) complex where it functions as a remodeling chaperone enabling the translocation of proteins from the ER to the cytoplasm for degradation by the proteosome. Interestingly, one of the proteins retrotranslocated by ERAD, a process necessary for its activation, is SKN-1A, the ER isoform of SKN-1. However, we discovered that SKN-1A is not activated by pathogen exposure in marked contrast to the cytoplasmic associated isoform, SKN-1C. Rather, loss of CDC-48 blocks the antioxidant response normally orchestrated by SKN-1C by strongly inducing the unfolded protein response (UPRER). The data is consistent with the model of these two pathways being mutually inhibitory and support the emerging paradigm in the field of coordinated cooperation between different stress responses.

Keywords:   Caenorhabditis elegans ; CDC-48; Nrf; SKN-1; infection; stress response

DOI:  https://doi.org/10.1093/genetics/iyae131
Cell Signal. 2024 Aug 19. pii: S0898-6568(24)00321-8. [Epub ahead of print] 111353

Unfolded proteins in the mitochondria activate HRI and inhibit mitochondrial protein translation.

Yongshu Wu, Yang Yang, Xiaodong Qin, Zhixiong Zhang, Munib Ullah, Yanmin Li, Zhidong Zhang.

  The mitochondrial unfolded protein response (UPRmt) is triggered through eIF2α phosphorylation in mammals. However, the mechanisms of UPRmt activation and the influence of eIF2α phosphorylation on mitochondrial protein translation remain unclear. In this study, we confirmed that the UPRmt is a rapid and specific stress response that occurs through pharmacological induction of eIF2α phosphorylation, along with the phosphorylation of eIF2α, ATF4, and CHOP. Moreover, with the upregulation of the expression of some chaperones, cytochrome P450 enzymes, and DDIT4, as determined by RNA-Seq and ribosome profiling, eIF2α phosphorylation was found to be essential for the expression of ATF4 and CHOP, after which ATF4 trafficked into the nucleus and initiated CHOP expression. In addition, the generation of ROS and mitochondrial morphology were not affected by the GTPP-induced UPRmt. Furthermore, we investigated the mechanism by which HRI kinase-mediated UPRmt is induced by mitochondrial unfolded proteins via CRISPR-Cas9 technology, mitochondrial recruitment of HRI and interactions with other proteins. Moreover, we confirmed that mitochondrial protein translation and mitochondrial protein import were inhibited through eIF2α phosphorylation with the accumulation of unfolded mitochondrial proteins. These findings reveal the molecular mechanism of the UPRmt and its impact on cellular protein translation, which will offer novel insights into the functions of the UPRmt, including its implications for human disease and pathobiology.

Keywords:  Heme-regulated inhibitor; Mitochondrial proteostasis; Mitochondrial unfolded protein response; eIF2α phosphorylation

DOI:  https://doi.org/10.1016/j.cellsig.2024.111353