bims-unfpre 2024-11-24 papers

bims-unfpre

Biomed News

on Unfolded protein response

Issue of 2024–11–24
six papers selected by
Susan Logue, University of Manitoba

Mutations in unfolded protein response regulator ATF6 cause hearing and vision loss syndrome.
Excess dietary sodium restores electrolyte and water homeostasis caused by loss of the endoplasmic reticulum molecular chaperone, GRP170, in the mouse nephron.
The critical role of endoplasmic reticulum stress and the stimulator of interferon genes (STING) pathway in kidney fibrosis.
Endoplasmic reticulum stress-mediated apoptosis and autophagy in osteoarthritis: from molecular mechanisms to therapeutic applications.
Autoinflammatory patients with Golgi-trapped CDC42 exhibit intracellular trafficking defects leading to STING hyperactivation and ER stress.
Mechanisms of the Mitochondrial Unfolded Protein Response in Caenorhabditis elegans and Mammals and Its Roles in Striated Muscles.

J Clin Invest. 2024 Nov 21. pii: e175562. [Epub ahead of print]

Mutations in unfolded protein response regulator ATF6 cause hearing and vision loss syndrome.

Eun-Jin Lee, Kyle Kim, Monica Sophia Diaz-Aguilar, Hyejung Min, Eduardo Chavez, Korina J Steinbergs, Lance A Safarta, Guirong Zhang, Allen F Ryan, Jonathan H Lin.

  Activating transcription factor 6 (Atf6) is a key regulator of the unfolded protein response (UPR) and is important for endoplasmic reticulum (ER) function and protein homeostasis in metazoan cells. Patients carrying loss-of-function ATF6 disease alleles develop the cone dysfunction disorder, achromatopsia. The impact of loss of ATF6 function on other cell types, organs, and diseases in people remains unclear. Here, we reported that progressive sensorineural hearing loss was a notable complaint in some patients carrying ATF6 disease alleles and that Atf6-/- mice also showed progressive auditory deficits affecting both genders. In mice with hearing deficits, we found disorganized stereocilia on hair cells and focal loss of outer hair cells. Transcriptomic analysis of Atf6-/- cochleae revealed marked induction of UPR, especially through the PERK arm. These findings identify ATF6 as an essential regulator of cochlear health and function. Furthermore, they supported that ATF6 inactivation in people causes progressive sensorineural hearing loss as part of a blindness-deafness genetic syndrome targeting hair cells and cone photoreceptors. Lastly, our genetic findings support ER stress as an important pathomechanism underlying cochlear damage and hearing loss with clinical implications for patient lifestyle modifications that minimize environmental/physiologic sources of ER stress to the ear.

Keywords:  Genetic diseases; Genetics; Molecular genetics; Ophthalmology; Retinopathy

DOI:  https://doi.org/10.1172/JCI175562
Am J Physiol Renal Physiol. 2024 Nov 18.

Excess dietary sodium restores electrolyte and water homeostasis caused by loss of the endoplasmic reticulum molecular chaperone, GRP170, in the mouse nephron.

Aidan W Porter, Hannah E Vorndran, Allison Marciszyn, Stephanie M Mutchler, Arohan R Subramanya, Thomas R Kleyman, Linda M Hendershot, Jeffrey L Brodsky, Teresa M Buck.

The maintenance of fluid and electrolyte homeostasis by the kidney requires proper folding and trafficking of ion channels and transporters in kidney epithelia. Each of these processes requires a specific subset of a diverse class of proteins termed molecular chaperones. One such chaperone is GRP170, which is an Hsp70-like, endoplasmic reticulum (ER)-localized chaperone that plays roles in protein quality control and protein folding in the ER. We previously determined that loss of GRP170 in the mouse nephron leads to hypovolemia, electrolyte imbalance, and rapid weight loss. In addition, GRP170-deficient mice develop an AKI-like phenotype, typified by tubular injury, elevation of kidney injury markers, and induction of the unfolded protein response (UPR). By using an inducible GRP170 knockout cellular model, we confirmed that GRP170 depletion induces the UPR, triggers apoptosis, and disrupts protein homeostasis. Based on these data, we hypothesized that UPR induction underlies hyponatremia and volume depletion in these rodents, and that these and other phenotypes might be rectified by sodium supplementation. To test this hypothesis, control and GRP170 tubule-specific knockout mice were provided a diet containing 8% sodium chloride. We discovered that sodium supplementation improved electrolyte imbalance and kidney injury markers in a sex-specific manner but was unable to restore weight or tubule integrity. These results are consistent with UPR induction contributing to the kidney injury phenotype in the nephron-specific GR170 knockout model and indicate that GRP170 function in kidney epithelia is essential to both maintain electrolyte balance and ER homeostasis.

Keywords: AKI; Chaperone; GRP170; UPR; proteostasis
Kidney Int. 2024 Nov 18. pii: S0085-2538(24)00788-9. [Epub ahead of print]

The critical role of endoplasmic reticulum stress and the stimulator of interferon genes (STING) pathway in kidney fibrosis.

Magaiver Andrade-Silva, Poonam Dhillon, Andrea Sanchez-Navarro, Dhanunjay Mukhi, Hailong Hu, Lakshmi P Kolligundla, Andrea Bergeson, Amin Abedini, Jonathan Levinsohn, Bernhard Dumoulin, Niels O S Câmara, Jonathan J Miner, Katalin Susztak.

  Endoplasmic Reticulum (ER) stress is a condition in which the ER is overwhelmed and unable to manage its protein load properly. The precise activation mechanisms and role of ER stress in kidney disease remain unclear. To study this, we performed unbiased transcriptomics analysis to demonstrate ER stress in kidneys of patients with chronic kidney disease and in mouse models of acute and chronic kidney injury (cisplatin and unilateral ureteral obstruction and reanalyzed previously published data on folic acid and mitochondrial transcription factor A(TFAM) knockout mice). Inhibiting the protein kinase RNA-like ER kinase (PERK) arm of ER stress but not activating transcription factor 6 or inositol-requiring enzyme 1, protected mice from kidney fibrosis. The stimulator of interferon genes (STING) was identified as an important upstream activator of ER stress in kidney tubule cells. STING and PERK were found to physically interact, and STING agonists induced PERK activation in kidney tubule cells. Mice with a STING activating mutation presented with ER stress and kidney fibroinflammation. We also generated mice with a tubule specific STING deletion that were resistant to ER stress and kidney fibrosis. Human kidney spatial transcriptomics highlighted a spatial correlation between STING, ER stress and fibrotic gene expression. Thus, our results indicate that STING is an important upstream regulator of PERK and ER stress in tubule cells during kidney fibrosis development.

Keywords:  PERK; chronic kidney disease; kidney fibrosis; nucleotide sensors; unfolded protein response

DOI:  https://doi.org/10.1016/j.kint.2024.10.021
Cell Stress Chaperones. 2024 Nov 19. pii: S1355-8145(24)00130-5. [Epub ahead of print]

Endoplasmic reticulum stress-mediated apoptosis and autophagy in osteoarthritis: from molecular mechanisms to therapeutic applications.

Yifan Lu, Jing Zhou, Hong Wang, Hua Gao, Eryu Ning, Zhiqiang Shao, Xing Yang, Yuefeng Hao.

  Osteoarthritis (OA) is characterized primarily by the degeneration of articular cartilage, with a high prevalence and disability rate. The functional phenotype of chondrocytes, as the sole cell type within cartilage, is vital for OA progression. Due to the avascular nature of cartilage and its limited regenerative capacity, repair following injury poses significant challenges. Various cellular stressors, including hypoxia, nutrient deprivation, oxidative stress, and collagen mutations, can lead to the accumulation of misfolded proteins in the endoplasmic reticulum (ER), resulting in ER stress (ERS). In response to restore ER homeostasis as well as cellular vitality and function, a series of adaptive mechanisms are triggered, including the unfolded protein response (UPR), ER-associated degradation (ERAD), and ER-phagy. Prolonged or severe ERS may exceed the adaptive capacity of cells, leading to dysregulation in apoptosis and autophagy-key pathogenic factors contributing to chondrocyte damage and OA progression. This review examines the relationship between ERS in OA chondrocytes and both apoptosis and autophagy in order to identify potential therapeutic targets and strategies for prevention and treatment of OA.

Keywords:  Apoptosis; Autophagy; Chondrocyte; Endoplasmic reticulum stress; Osteoarthritis

DOI:  https://doi.org/10.1016/j.cstres.2024.11.005
Nat Commun. 2024 Nov 16. 15(1): 9940

Autoinflammatory patients with Golgi-trapped CDC42 exhibit intracellular trafficking defects leading to STING hyperactivation and ER stress.

Alberto Iannuzzo, Selket Delafontaine, Rana El Masri, Rachida Tacine, Giusi Prencipe, Masahiko Nishitani-Isa, Rogier T A van Wijck, Farzana Bhuyan, Adriana A de Jesus Rasheed, Simona Coppola, Paul L A van Daele, Antonella Insalaco, Raphaela Goldbach-Mansky, Takahiro Yasumi, Marco Tartaglia, Isabelle Meyts, Jérôme Delon.

Most autoinflammatory diseases are caused by mutations in innate immunity genes. Previously, four variants in the RHO GTPase CDC42 were discovered in patients affected by syndromes generally characterized by neonatal-onset of cytopenia and auto-inflammation, including hemophagocytic lymphohistiocytosis and rash in the most severe form (NOCARH syndrome). However, the mechanisms responsible for these phenotypes remain largely elusive. Here, we show that the recurrent p.R186C CDC42 variant, which is trapped in the Golgi apparatus, elicits a block in both anterograde and retrograde transports. Consequently, it favours STING accumulation in the Golgi in a COPI-dependent manner. This is also observed for the other Golgi-trapped p.*192 C*24 CDC42 variant, but not for the p.Y64C and p.C188Y variants that do not accumulate in the Golgi. We demonstrate that the two Golgi-trapped CDC42 variants are the only ones that exhibit overactivation of the STING pathway and the type I interferon response, and elicit endoplasmic reticulum stress. Consistent with these results, patients carrying Golgi-trapped CDC42 mutants present very high levels of circulating IFNα at the onset of their disease. In conclusion, we report further mechanistic insights on the impact of the Golgi-trapped CDC42 variants. This increase in STING activation provides a rationale for combination treatments for these severe cases.

DOI: https://doi.org/10.1038/s41467-024-54294-y
Aging Dis. 2024 Nov 18.

Mechanisms of the Mitochondrial Unfolded Protein Response in Caenorhabditis elegans and Mammals and Its Roles in Striated Muscles.

Tongxiao Luan, Song Hu, Weihong Nie, Jia Liu, Li Jia, Shan Wang, Jing Zhou, Nina An, Yuting Duan, Aohua Wang, Mengru Xu, Yongjun Mao.

Throughout the course of evolution, organisms and cells have evolved a suite of mechanisms to manage persistent stimuli, thereby preserving cellular and organismal homeostasis. Upon detecting stress signals, cells activate a transcriptional response termed the mitochondrial unfolded protein response (UPRmt). This response is crucial for maintaining protein homeostasis, facilitating mitochondrial function recovery, promoting cell survival, and ultimately influencing lifespan. Striated muscles play a pivotal role in oxygen supply, movement, and metabolism. The aging of these muscles can lead to heart failure, arrhythmias, and sarcopenia, significantly impacting quality of life and lifespan. Given the intimate connection between UPRmt and striated muscle aging, UPRmt emerges as a potential therapeutic target for mitigating the effects of striated muscle aging. In this review, we delve into the role of UPRmt in striated muscle aging, drawing upon the extant molecular regulatory mechanisms of UPRmt. This exploration may enhance our understanding of the underlying mechanisms of striated muscle aging and aid in the identification of potential drug targets.

DOI: https://doi.org/10.14336/AD.2024.1019