bims-ershed 2022-12-04 papers

Cell Rep. 2022 Nov 29. pii: S2211-1247(22)01617-5. [Epub ahead of print]41(9): 111739

Neuronal IRE-1 coordinates an organism-wide cold stress response by regulating fat metabolism.

Reut Dudkevich, Jhee Hong Koh, Caroline Beaudoin-Chabot, Cenk Celik, Ilana Lebenthal-Loinger, Sarit Karako-Lampert, Syed Ahmad-Albukhari, Guillaume Thibault, Sivan Henis-Korenblit.

Cold affects many aspects of biology, medicine, agriculture, and industry. Here, we identify a conserved endoplasmic reticulum (ER) stress response, distinct from the canonical unfolded protein response, that maintains lipid homeostasis during extreme cold. We establish that the ER stress sensor IRE-1 is critical for resistance to extreme cold and activated by cold temperature. Specifically, neuronal IRE-1 signals through JNK-1 and neuropeptide signaling to regulate lipid composition within the animal. This cold-response pathway can be bypassed by dietary supplementation with unsaturated fatty acids. Altogether, our findings define an ER-centric conserved organism-wide cold stress response, consisting of molecular neuronal sensors, effectors, and signaling moieties, which control adaptation to cold conditions in the organism. Better understanding of the molecular basis of this stress response is crucial for the optimal use of cold conditions on live organisms and manipulation of lipid saturation homeostasis, which is perturbed in human pathologies.

Keywords: C. elegans; CP: Metabolism; IRE-1; IRE1; JNK; cell non-autonomous stress response; cold stress; endoplasmic reticulum; fat metabolism; lipids; unfolded protein response

DOI: https://doi.org/10.1016/j.celrep.2022.111739

Indian J Microbiol. 2022 Dec;62(4): 634-640

Pharmacological Manipulation of UPR: Potential Antiviral Strategy Against Chikungunya Virus.

Nishtha Agrawal, Sanjesh Saini, Madhu Khanna, Gagan Dhawan, Uma Dhawan.

Abstract: Viruses invade the host cells and maneuver the cellular translation machinery to translate the viral proteins in substantial amounts, which may disturb Endoplasmic Reticulum homeostasis leading to induction of Unfolded Protein Response (UPR), a host response pathway involved in viral pathogenesis. Here, we investigated the effect of UPR pathways on the pathogenesis of chikungunya virus infection. We observed that chikungunya virus mediated the modulation of UPR. A positive modulation was observed in the activation of IRE1 and ATF6 branch while the PERK branch of UPR observed suppressed upon virus infection. We further investigated the effect of the inhibition of UPR pathways on chikungunya virus replication using inhibitors for each branch. Cells treated with 3-ethoxy-5,6-dibromosalicylaldehyde (IRE1 inhibitor) and AEBSF (ATF6 inhibitor) significantly inhibits the viral replication process. This study has provided a novel perspective in designing antivirals against chikungunya virus.
Graphical Abstract:
Supplementary Information: The online version contains supplementary material available at 10.1007/s12088-022-01046-5.

Keywords: 3-ethoxy-5,6-dibromosalicylaldehyde; AEBSF; Chikungunya virus; ER stress; Unfolded protein response; Virus replication

DOI: https://doi.org/10.1007/s12088-022-01046-5

Cell Stress Chaperones. 2022 Nov 30.

Crosstalk between endoplasmic reticulum and cytosolic unfolded protein response in tomato.

Karin Löchli, Emma Torbica, Misgana Haile-Weldeslasie, Deborah Baku, Aatika Aziz, Daniela Bublak, Sotirios Fragkostefanakis.

Conditions that cause proteotoxicity like high temperature trigger the activation of unfolded protein response (UPR). The cytosolic (CPR) and endoplasmic reticulum (ER) UPR rely on heat stress transcription factor (HSF) and two members of the basic leucine zipper (bZIP) gene family, respectively. In tomato, HsfA1a is the master regulator of CPR. Here, we identified the core players of tomato ER-UPR including the two central transcriptional regulators, namely bZIP28 and bZIP60. Interestingly, the induction of ER-UPR genes and the activation of bZIP60 are altered in transgenic plants where HsfA1a is either overexpressed (A1aOE) or suppressed (A1CS), indicating an interplay between CPR and ER-UPR systems. Several ER-UPR genes are differentially expressed in the HsfA1a transgenic lines either exposed to heat stress or to the ER stress elicitor tunicamycin (TUN). The ectopic expression of HsfA1a is associated with higher tolerance against TUN. On the example of the ER-resident Hsp70 chaperone BIP3, we show that the presence of cis-elements required for HSF and bZIP regulation serves as a putative platform for the co-regulation of these genes by both CPR and ER-UPR mechanisms, in the case of BIP3 in a stimulatory manner under high temperatures. In addition, we show that the accumulation of HsfA1a results in higher levels of three ATG genes and a more sensitized induction of autophagy in response to ER stress which also supports the increased tolerance to ER stress of the A1aOE line. These findings provide a basis for the coordination of protein homeostasis in different cellular compartments under stress conditions.

Keywords: Autophagy; Endoplasmic reticulum; Heat shock proteins; Heat stress transcription factors; Unfolded protein response; bZIP

DOI: https://doi.org/10.1007/s12192-022-01316-7

J Cell Sci. 2022 Dec 01. pii: jcs259634. [Epub ahead of print]135(23):

Mitochondria-associated niches in health and disease.

Mateus Milani, Philippe Pihán, Claudio Hetz.

The appreciation of the importance of interorganelle contacts has steadily increased over the past decades. Advances in imaging, molecular biology and bioinformatic techniques allowed the discovery of new mechanisms involved in the interaction and communication between organelles, providing novel insights into the inner works of a cell. In this Review, with the mitochondria under the spotlight, we discuss the most recent findings on the mechanisms mediating the communication between organelles, focusing on Ca2+ signaling, lipid exchange, cell death and stress responses. Notably, we introduce a new integrative perspective to signaling networks that is regulated by interorganelle interactions - the mitochondria-associated niches - focusing on the link between the molecular determinants of contact sites and their functional outputs, rather than simply physical and structural communication. In addition, we highlight the neuropathological and metabolic implications of alterations in mitochondria-associated niches and outline how this concept might improve our understanding of multi-organelle interactions.

Keywords: Apoptosis; Bioenergetics; MAMs; Mitochondria; Mitochondria-associated membranes; Stress responses

DOI: https://doi.org/10.1242/jcs.259634

Theranostics. 2022 ;12(17): 7289-7306

C9orf72 regulates the unfolded protein response and stress granule formation by interacting with eIF2α.

Wenzhong Zheng, Kexin Wang, Yachen Wu, Ge Yan, Chi Zhang, Zhiqiang Li, Lianrong Wang, Shi Chen.

Rationale: A C9orf72 hexanucleotide repeat expansion (GGGGCC) is the most common genetic origin of amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). Haploinsufficiency of C9orf72 has been proposed as a possible disease mechanism (loss-of-function mechanism). Additionally, the aberrantly activated unfolded protein response (UPR) and stress granule (SG) formation are associated with the etiopathology of both ALS and FTD. However, the molecular determinants in this pathogenesis are not well characterized. Methods: We performed an immunoprecipitation-mass spectrometry (IP-MS) assay to identify potential proteins interacting with the human C9orf72 protein. We used C9orf72 knockout cell and rat models to determine the roles of C9orf72 in translation initiation and the stress response. Results: Here, we show that C9orf72, which is genetically and pathologically related to ALS and FTD, interacts with eukaryotic initiation factor 2 subunit alpha (eIF2α) and regulates its function in translation initiation. C9orf72 knockout weakens the interaction between eIF2α and eIF2B5, leading to global translation inhibition. Moreover, the loss of C9orf72 results in primary ER stress with activated UPR in rat spleens, which is one of the causes of splenomegaly with inflammation in C9orf72 -/- rats. Finally, C9orf72 delays SG formation by interacting with eIF2α in stressed cells. Conclusions: In summary, these data reveal that C9orf72 modulates translation initiation, the UPR and SG formation, which have implications for understanding ALS/FTD pathogenesis.

Keywords: C9orf72; eIF2α; stress granule formation; translation initiation; unfolded protein response

DOI: https://doi.org/10.7150/thno.76138