Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the UPR in models of neurodegeneration

Vidal, René L.; Sepúlveda, Denisse; Troncoso-Escudero, Paulina; García-Huerta, Paula; González, Constanza; Plate, Lars; Jerez, Carolina; Cánovas, José Luis; Rivera, Claudia A; Castillo, Valentina; Cisternas, Marisol; Leal, Sirley; Martínez, Alexis; Grandjean, Julia M. D.; Donzelli, Sonia; Lashuel, Hilal A.; Martin, Alberto J. M.; Latapiat, Verónica; Matus, Soledad; Sardi, S. Pablo; Wiseman, R. Luke; Hetz, Claudio

doi:10.1016/j.ymthe.2021.01.033

Cited by 28 publications

(14 citation statements)

References 140 publications

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“…These results are consistent with prior work showing that ATF6 induction causes upregulation of fewer transcripts than XBP1s [41,49], as well as with the ability of XBP1s and ATF6 to synergistically upregulate a larger set of transcripts than either transcription factor alone, likely via heterodimerization of the transcription factors [41,50,51]. Taken together, our RNA-Seq results show that we can access four distinctive ER proteostasis environments for Env mutational tolerance experiments via chemical genetical control of XBP1s and ATF6 (basal, +XBP1s, +ATF6, and +XBP1s/+ATF6).…”

Section: Chemical Genetic Control Of Er Proteostasis Network Composition During Hiv Infectionsupporting

confidence: 91%

The Host Cell’s Endoplasmic Reticulum Proteostasis Network Profoundly Shapes the Protein Sequence Space Accessible to HIV Envelope

Yoon

Nekongo

Patrick

et al. 2021

Preprint

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The sequence space accessible to evolving proteins can be enhanced by cellular chaperones that assist biophysically defective clients in navigating complex folding landscapes. It is also possible, however, for proteostasis mechanisms that promote strict quality control to greatly constrain accessible protein sequence space. Unfortunately, most efforts to understand how proteostasis mechanisms influence evolution rely on artificial inhibition or genetic knockdown of specific chaperones. The few experiments that perturb quality control pathways also generally modulate the levels of only individual quality control factors. Here, we use chemical genetic strategies to tune proteostasis networks via natural stress response pathways that regulate levels of entire suites of chaperones and quality control mechanisms. Specifically, we upregulate the unfolded protein response (UPR) to test the hypothesis that the host endoplasmic reticulum (ER) proteostasis network shapes the sequence space accessible to human immunodeficiency virus-1 (HIV) envelope (Env) protein. Elucidating factors that enhance or constrain Env sequence space is critical because Env evolves extremely rapidly, yielding HIV strains with antibody and drug escape mutations. We find that UPR-mediated upregulation of ER proteostasis factors, particularly those controlled by the IRE1-XBP1s UPR arm, globally reduces Env mutational tolerance. Conserved, functionally important Env regions exhibit the largest decreases in mutational tolerance upon XBP1s activation. This phenomenon likely reflects strict quality control endowed by XBP1s-mediated remodeling of the ER proteostasis environment. Intriguingly and in contrast, specific regions of Env, including regions targeted by broadly neutralizing antibodies, display enhanced mutational tolerance when XBP1s is activated, hinting at a role for host proteostasis network hijacking in potentiating antibody escape. These observations reveal a key function for proteostasis networks in decreasing instead of expanding the sequence space accessible to client proteins, while also demonstrating that the host ER proteostasis network profoundly shapes the mutational tolerance of Env in ways that could have important consequences for HIV adaptation.

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Section: Chemical Genetic Control Of Er Proteostasis Network Composition During Hiv Infectionsupporting

confidence: 91%

The Host Cell’s Endoplasmic Reticulum Proteostasis Network Profoundly Shapes the Protein Sequence Space Accessible to HIV Envelope

Yoon

Nekongo

Patrick

et al. 2021

Preprint

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“…Taken together with the previously discussed protective function of XBP1 in PD, signaling through both the PERK-UPR ER and the ATF6-UPR ER appear to augment neuroprotective programs in PD models. This conclusion is supported by a recent study demonstrating that viral-mediated delivery of an XBP1/ATF6 fusion protein promotes degradation of α-syn aggregates in vivo and protects dopaminergic neurons following 6-OHDA treatment (Vidal et al, 2021). Therefore, the promotion of UPR ER genes downstream of XBP1 and ATF6, including chaperones and degradative pathways, displays neuroprotective potential in PD pathogenesis.…”

Section: The Endoplasmic Reticulum Unfolded Protein Response In Parki...mentioning

confidence: 60%

“…Whether this activation represents protective or detrimental signaling is complex. Activation of the UPR ER by virally delivered XBP1 or XBP1/ATF6 fusion protein appears to be protective across multiple NDD contexts (Sado et al, 2009;Zuleta et al, 2012;Cissé et al, 2017;Vidal et al, 2021). However, it is also clear that dysregulated UPR ER signaling can drive pathogenesis under certain disease states, and so future work aimed at better defining both protective and detrimental UPR ER signatures in disease models will be critical moving forward to allow targeting of therapies to the appropriate disease populations.…”

Section: Discussionmentioning

confidence: 99%

The Unfolded Protein Responses in Health, Aging, and Neurodegeneration: Recent Advances and Future Considerations

Wodrich

Scott

Shukla

et al. 2022

Front. Mol. Neurosci.

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Aging and age-related neurodegeneration are both associated with the accumulation of unfolded and abnormally folded proteins, highlighting the importance of protein homeostasis (termed proteostasis) in maintaining organismal health. To this end, two cellular compartments with essential protein folding functions, the endoplasmic reticulum (ER) and the mitochondria, are equipped with unique protein stress responses, known as the ER unfolded protein response (UPRER) and the mitochondrial UPR (UPRmt), respectively. These organellar UPRs play roles in shaping the cellular responses to proteostatic stress that occurs in aging and age-related neurodegeneration. The loss of adaptive UPRER and UPRmt signaling potency with age contributes to a feed-forward cycle of increasing protein stress and cellular dysfunction. Likewise, UPRER and UPRmt signaling is often altered in age-related neurodegenerative diseases; however, whether these changes counteract or contribute to the disease pathology appears to be context dependent. Intriguingly, altering organellar UPR signaling in animal models can reduce the pathological consequences of aging and neurodegeneration which has prompted clinical investigations of UPR signaling modulators as therapeutics. Here, we review the physiology of both the UPRER and the UPRmt, discuss how UPRER and UPRmt signaling changes in the context of aging and neurodegeneration, and highlight therapeutic strategies targeting the UPRER and UPRmt that may improve human health.

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“…More recently, co-expression of XBP1 and ATF6 in a fusion protein by AAV-based delivery showed a more potent effect in the neuroprotection and anti-aggregation of mis-folded proteins than XBP1 or ATF6 alone in preclinical models for PD and HD. This suggests a cooperative action of XBP1 and ATF6 in enhancing the folding capacity of the ER and promoting cell survival under disease settings [ 281 ]. Overexpression of XBP1 by AAV-mediated delivery may be a promising therapeutic strategy readily tested in alcoholic pancreatitis because XBP1 has been implicated to have a beneficial role in alcohol-induced pancreatic damages in animals [ 74 ].…”

Section: Potential Treatment Of Alcoholic Pancreatitis By Targeting Er Stress and Uprmentioning

confidence: 99%

Targeting Endoplasmic Reticulum Stress as an Effective Treatment for Alcoholic Pancreatitis

Wen

Luo

2022

Biomedicines

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Pancreatitis and alcoholic pancreatitis are serious health concerns with an urgent need for effective treatment strategies. Alcohol is a known etiological factor for pancreatitis, including acute pancreatitis (AP) and chronic pancreatitis (CP). Excessive alcohol consumption induces many pathological stress responses; of particular note is endoplasmic reticulum (ER) stress and adaptive unfolded protein response (UPR). ER stress results from the accumulation of unfolded/misfolded protein in the ER and is implicated in the pathogenesis of alcoholic pancreatitis. Here, we summarize the possible mechanisms by which ER stress contributes to alcoholic pancreatitis. We also discuss potential approaches targeting ER stress and UPR in developing novel therapeutic strategies for the disease.

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Enforced dimerization between XBP1s and ATF6f enhances the protective effects of the UPR in models of neurodegeneration

Cited by 28 publications

References 140 publications

The Host Cell’s Endoplasmic Reticulum Proteostasis Network Profoundly Shapes the Protein Sequence Space Accessible to HIV Envelope

The Host Cell’s Endoplasmic Reticulum Proteostasis Network Profoundly Shapes the Protein Sequence Space Accessible to HIV Envelope

The Unfolded Protein Responses in Health, Aging, and Neurodegeneration: Recent Advances and Future Considerations

Targeting Endoplasmic Reticulum Stress as an Effective Treatment for Alcoholic Pancreatitis

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