bims-ershed 2022-10-23 papers

Issue of 2022‒10‒23
five papers selected by
Matías Eduardo González Quiroz
Worker’s Hospital

Proc Natl Acad Sci U S A. 2022 Oct 25. 119(43): e2123187119

Disruption of proteostasis causes IRE1 mediated reprogramming of alveolar epithelial cells.

Jeremy Katzen, Luis Rodriguez, Yaniv Tomer, Apoorva Babu, Ming Zhao, Aditi Murthy, Paige Carson, Matthew Barrett, Maria C Basil, Justine Carl, John P Leach, Michael Morley, Matthew D McGraw, Surafel Mulugeta, Timothy Pelura, Glenn Rosen, Edward E Morrisey, Michael F Beers.

Disruption of alveolar type 2 cell (AEC2) protein quality control has been implicated in chronic lung diseases, including pulmonary fibrosis (PF). We previously reported the in vivo modeling of a clinical surfactant protein C (SP-C) mutation that led to AEC2 endoplasmic reticulum (ER) stress and spontaneous lung fibrosis, providing proof of concept for disruption to proteostasis as a proximal driver of PF. Using two clinical SP-C mutation models, we have now discovered that AEC2s experiencing significant ER stress lose quintessential AEC2 features and develop a reprogrammed cell state that heretofore has been seen only as a response to lung injury. Using single-cell RNA sequencing in vivo and organoid-based modeling, we show that this state arises de novo from intrinsic AEC2 dysfunction. The cell-autonomous AEC2 reprogramming can be attenuated through inhibition of inositol-requiring enzyme 1 (IRE1α) signaling as the use of an IRE1α inhibitor reduced the development of the reprogrammed cell state and also diminished AEC2-driven recruitment of granulocytes, alveolitis, and lung injury. These findings identify AEC2 proteostasis, and specifically IRE1α signaling through its major product XBP-1, as a driver of a key AEC2 phenotypic change that has been identified in lung fibrosis.

Keywords: ER stress; quality control; surfactant protein C; transitional cell; unfolded protein response

DOI: https://doi.org/10.1073/pnas.2123187119

Nat Commun. 2022 Oct 19. 13(1): 5889

The unfolded protein response reverses the effects of glucose on lifespan in chemically-sterilized C. elegans.

Caroline Beaudoin-Chabot, Lei Wang, Cenk Celik, Aishah Tul-Firdaus Abdul Khalid, Subhash Thalappilly, Shiyi Xu, Jhee Hong Koh, Venus Wen Xuan Lim, Ann Don Low, Guillaume Thibault.

Metabolic diseases often share common traits, including accumulation of unfolded proteins in the endoplasmic reticulum (ER). Upon ER stress, the unfolded protein response (UPR) is activated to limit cellular damage which weakens with age. Here, we show that Caenorhabditis elegans fed a bacterial diet supplemented high glucose at day 5 of adulthood (HGD-5) extends their lifespan, whereas exposed at day 1 (HGD-1) experience shortened longevity. We observed a metabolic shift only in HGD-1, while glucose and infertility synergistically prolonged the lifespan of HGD-5, independently of DAF-16. Notably, we identified that UPR stress sensors ATF-6 and PEK-1 contributed to the longevity of HGD-5 worms, while ire-1 ablation drastically increased HGD-1 lifespan. Together, we postulate that HGD activates the otherwise quiescent UPR in aged worms to overcome ageing-related stress and restore ER homeostasis. In contrast, young animals subjected to HGD provokes unresolved ER stress, conversely leading to a detrimental stress response.

DOI: https://doi.org/10.1038/s41467-022-33630-0

J Am Soc Nephrol. 2022 Oct 21. pii: ASN.2021091180. [Epub ahead of print]

XBP1 Activation Reduces Severity of Polycystic Kidney Disease due to a Nontruncating Polycystin-1 Mutation in Mice.

Matteus Krappitz, Rishi Bhardwaj, Ke Dong, Tobias Staudner, Duygu Elif Yilmaz, Carlotta Pioppini, Parisa Westergerling, David Ruemmele, Till Hollmann, Thuy Anh Nguyen, Yiqiang Cai, Anna-Rachel Gallagher, Stefan Somlo, Sorin Fedeles.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in Pkd1 and Pkd2. They encode the polytopic integral membrane proteins polycystin-1 (PC1) and polycystin-2 (PC2), respectively, which are expressed on primary cilia. Formation of kidney cysts in ADPKD starts when a somatic second hit mechanism inactivates the wild-type Pkd allele. Approximately one quarter of families with ADPDK due to Pkd1 have germline nonsynonymous amino acid substitution (missense) mutations. A subset of these mutations is hypomorphic, retaining some residual PC1 function. Previous studies have shown that the highly conserved Ire1α-XBP1 pathway of the unfolded protein response can modulate levels of functional PC1 in the presence of mutations in genes required for post-translational maturation of integral membrane proteins. We examine how activity of the endoplasmic reticulum chaperone-inducing transcription factor XBP1 affects ADPKD in a murine model with missense Pkd1.METHODS: We engineered a Pkd1 REJ domain missense murine model, Pkd1R2216W , on the basis of the orthologous human hypomorphic allele Pkd1R2220W , and examined the effects of transgenic activation of XBP1 on ADPKD progression.
RESULTS: Expression of active XBP1 in cultured cells bearing PC1R2216W mutations increased levels and ciliary trafficking of PC1R2216W. Mice homozygous for Pkd1R2216W or heterozygous for Pkd1R2216W in trans with a conditional Pkd1fl allele exhibit severe ADPKD following inactivation in neonates or adults. Transgenic expression of spliced XBP1 in tubule segments destined to form cysts reduced cell proliferation and improved Pkd progression, according to structural and functional parameters.
CONCLUSIONS: Modulating ER chaperone function through XBP1 activity improved Pkd in a murine model of PC1, suggesting therapeutic targeting of hypomorphic mutations.

Keywords: Ire1α-XBP1 pathway; chaperone; genetic renal disease; mutation; polycystic kidney disease; polycystin-1; protein folding; unfolded protein response

DOI: https://doi.org/10.1681/ASN.2021091180

J Biol Chem. 2022 Oct 13. pii: S0021-9258(22)01035-3. [Epub ahead of print] 102592

Features and factors that dictate if terminating ribosomes cause or counteract nonsense-mediated mRNA decay.

Caleb M Embree, Rabab Abu Alhasan, Guramrit Singh.

Nonsense-mediated mRNA decay (NMD) is a quality control pathway in eukaryotes that continuously monitors mRNA transcripts to ensure truncated polypeptides are not produced. The expression of many normal mRNAs that encode full-length polypeptides is also regulated by this pathway. Such transcript surveillance by NMD is intimately linked to translation termination. When a ribosome terminates translation at a normal termination codon (NTC), NMD is not activated, and mRNA can undergo repeated rounds of translation. On the other hand, when translation termination is deemed abnormal, such as that on a premature termination codon (PTC), it leads to a series of poorly understood events involving the NMD pathway, which destabilizes the transcript. In this review, we summarize our current understanding of how the NMD machinery interfaces with the translation termination factors to initiate NMD. We also discuss a variety of cis-acting sequence contexts and trans-acting factors that can cause readthrough, ribosome re-initiation, or ribosome frameshifting at stop codons predicted to induce NMD. These alternative outcomes can lead to the ribosome translating downstream of such stop codons and hence the transcript escaping NMD. NMD escape via these mechanisms can have wide-ranging implications on human health, from being exploited by viruses to hijack host cell systems to being harnessed as potential therapeutic possibilities to treat genetic diseases.

Keywords: nonsense meditated mRNA decay; nonsense mutations; ribosome; translation; translation termination

DOI: https://doi.org/10.1016/j.jbc.2022.102592

Pharmacol Res. 2022 Oct 14. pii: S1043-6618(22)00459-5. [Epub ahead of print]185 106513

Blocking the cytohesin-2/ARF1 axis by SecinH3 ameliorates osteoclast-induced bone loss via attenuating JNK-mediated IRE1 endoribonuclease activity.

Yimin Dong, Kehan Song, Pengju Wang, Jiachao Guo, Honglei Kang, Xi Tan, Binxiang Zhu, Renpeng Peng, Meipeng Zhu, Kaixu Yu, Qian Guo, Hanfeng Guan, Feng Li.

cytohesin-2 is a guanine nucleotide exchange factor to activate ARF1 and ARF6, which are involved in various biological processes, including signal transduction, cell differentiation, cell structure organization, and survival. Nevertheless, there is a lack of evidence revealing the role of cytohesin-2 in osteoclast differentiation and in the development of osteoporosis. In this study, we find cytohesin-2 and ARF1 positively regulate osteoclast differentiation and function. Blocking the cytohesin-2 /ARF1 axis with SecinH3 or by genetic silencing of cytohesin-2 inhibits osteoclast formation and function in vitro. In vivo treatment with SecinH3 ameliorates ovariectomy-induced osteoporosis. Mechanistically, RNA-sequencing combined with molecular biological methodologies reveal that the regulatory function of cythohesin-2/ARF1 axis in osteoclast differentiation is mainly dependent on activating the JNK pathway. Further, in addition to the common viewpoint that JNK is activated by IRE1 via its kinase activity, we found that JNK can act upstream and regulate the endoribonuclease activity of IRE1 to promote XBP1 splicing. Both SecinH3 and silencing of cytohesin-2 inhibit JNK activation and IRE1 endoribonuclease activity, leading to the suppression of osteoclast differentiation. Taken together, our findings add new insights into the regulation between JNK and IRE1, and reveal that inhibiting the cytohesin-2/ARF1/JNK/IRE1 axis might represent a potential new strategy for the treatment of post-menopause osteoporosis.

Keywords: 4μ8C (PubChem CID: 12934390); ARF1; Cytohesin-2; Endoribonuclease activity; IRE1; JNK; NAV-2729 (PubChem CID: 2257249); Osteoclast; SP600125 (PubChem CID: 8515); SecinH3; SecinH3 (PubChem CID: 1029232); Thapsigargin (PubChem CID: 446378)

DOI: https://doi.org/10.1016/j.phrs.2022.106513