bims-ershed 2023-04-09 papers

Mol Ther. 2023 Apr 03. pii: S1525-0016(23)00161-2. [Epub ahead of print]

The unfolded protein response transcription factor XBP1s ameliorates Alzheimer's disease by improving synaptic function and proteostasis.

Alteration in the buffering capacity of the proteostasis network is an emerging feature of Alzheimer's disease (AD), highlighting the occurrence of endoplasmic reticulum (ER) stress. The unfolded protein response (UPR) is the main adaptive pathway to cope with protein folding stress at the ER. Inositol requiring enzyme-1 (IRE1) operates as a central ER stress sensor, enabling the establishment of adaptive and repair programs through the control of the expression of the transcription factor X-Box binding protein 1 (XBP1). To artificially enforce the adaptive capacity of the UPR in the AD brain, we developed strategies to express the active form of XBP1 in the brain. Overexpression of XBP1 in the nervous system using transgenic mice reduced the load of amyloid deposits and preserved synaptic and cognitive function. Moreover, local delivery of XBP1 into the hippocampus of an AD mice using adeno-associated vectors improved different AD features. XBP1 expression corrected a large proportion of the proteomic alterations observed in the 5xFAD model, restoring the levels of several synaptic proteins and factors involved in actin cytoskeleton regulation and axonal growth. Our results illustrate the therapeutic potential of targeting UPR-dependent gene expression programs as a strategy to ameliorate AD features and sustain synaptic function.

DOI: https://doi.org/10.1016/j.ymthe.2023.03.028

Aging Dis. 2023 Apr 01. 14(2): 350-369

X-box Binding Protein 1: An Adaptor in the Pathogenesis of Atherosclerosis.

Tao Wang, Jia Zhou, Xiao Zhang, Yujie Wu, Kehan Jin, Yilin Wang, Ran Xu, Ge Yang, Wenjing Li, Liqun Jiao.

Atherosclerosis (AS), the formation of fibrofatty lesions in the vessel wall, is the primary cause of heart disease and stroke and is closely associated with aging. Disrupted metabolic homeostasis is a primary feature of AS and leads to endoplasmic reticulum (ER) stress, which is an abnormal accumulation of unfolded proteins. By orchestrating signaling cascades of the unfolded protein response (UPR), ER stress functions as a double-edged sword in AS, where adaptive UPR triggers synthetic metabolic processes to restore homeostasis, whereas the maladaptive response programs the cell to the apoptotic pathway. However, little is known regarding their precise coordination. Herein, an advanced understanding of the role of UPR in the pathological process of AS is reviewed. In particular, we focused on a critical mediator of the UPR, X-box binding protein 1 (XBP1), and its important role in balancing adaptive and maladaptive responses. The XBP1 mRNA is processed from the unspliced isoform (XBP1u) to the spliced isoform of XBP1 (XBP1s). Compared with XBP1u, XBP1s predominantly functions downstream of inositol-requiring enzyme-1α (IRE1α) and transcript genes involved in protein quality control, inflammation, lipid metabolism, carbohydrate metabolism, and calcification, which are critical for the pathogenesis of AS. Thus, the IRE1α/XBP1 axis is a promising pharmaceutical candidate against AS.

Keywords: IRE1α; XBP1; atherosclerosis; endoplasmic reticulum stress; unfolded protein response

DOI: https://doi.org/10.14336/AD.2022.0824

Front Cell Dev Biol. 2023 ;11 1089728

Normal tissue homeostasis and impairment of selective inflammatory responses in dendritic cells deficient for ATF6α.

Francisca Gutiérrez-Ballesteros, Jonathan Morales-Reyes, Dominique Fernández, Antonia Geisse, Amada Arcaya, Felipe Flores-Santibañez, María Rosa Bono, Fabiola Osorio.

The initiation of adaptive immunity relies on the performance of dendritic cells (DCs), which are specialized leukocytes with professional antigen presenting capabilities. As such, the molecular mechanisms safeguarding DC homeostasis are matter of intense research. Sensors of the unfolded protein response (UPR) of the endoplasmic reticulum, a three-pronged signaling pathway that maintains the fidelity of the cellular proteome, have emerged as regulators of DC biology. The archetypical example is the IRE1/XBP1s axis, which supports DC development and survival of the conventional type 1 DC (cDC1) subtype. However, the role of additional UPR sensors in DC biology, such as the ATF6α branch, has not been clearly elucidated. Even though Xbp1 is transcriptionally induced by ATF6α under ER stress, it is unclear if cDCs also co-opt the ATF6α branch in tissues. Here, we examine the role of ATF6α in cDC homeostasis in vivo and upon innate stimulation in vitro. In steady state, animals lacking ATF6α in CD11c+ cells (Itgax Cre x Atf6 fl/fl mice) display normal cDC frequencies in spleen, intestine, liver, and lung. Also, ATF6α deficient cDCs express normal levels of Xbp1 mRNA and additional UPR components. However, a reduction of lung monocytes is observed in Itgax Cre x Atf6 fl/fl conditional deficient animals suggesting that ATF6α may play a role in the biology of monocyte subsets. Notably, in settings of DC activation, ATF6α contributes to the production of IL-12 and IL-6 to inflammatory stimuli. Thus, although ATF6α may be dispensable for tissue cDC homeostasis in steady state, the transcription factor plays a role in the acquisition of selective immunogenic features by activated DCs.

Keywords: ATF6; IL-12; IL-6; dendritic cells; immunity; proinflammatory cytokines; tissues; unfolded protein response

DOI: https://doi.org/10.3389/fcell.2023.1089728

FASEB J. 2023 05;37(5): e22902

Emerging evidence for poxvirus-mediated unfolded protein response: Lumpy skin disease virus maintains self-replication by activating PERK and IRE1 signaling.

Jinlong Tan, Yinju Liu, Fan Yang, Guohua Chen, Yongxiang Fang, Xiaobing He, Zhongzi Lou, Huaijie Jia, Zhizhong Jing, Weike Li.

The monkeypox epidemic has attracted global attention to poxviruses. The cytoplasmic replication of poxviruses requires extensive protein synthesis, challenging the capacity of the endoplasmic reticulum (ER). However, the role of the ER in the life cycle of poxviruses is unclear. In this study, we demonstrate that infection with the lumpy skin disease virus (LSDV), a member of the poxvirus family, causes ER stress in vivo and in vitro, further facilitating the activation of the unfolded protein response (UPR). Although UPR activation aids in the restoration of the cellular environment, its significance in the LSDV life cycle remains unclear. Furthermore, the significance of ER imbalance for viral replication is also unknown. We show that LSDV replication is hampered by an unbalanced ER environment. In addition, we verify that the LSDV replication depends on the activation of PERK-eIF2α and IRE1-XBP1 signaling cascades rather than ATF6, implying that global translation and reduced XBP1 cleavage are deleterious to LSDV replication. Taken together, these findings indicate that LSDV is involved in the repression of global translational signaling, ER chaperone transcription, and ATF6 cleavage from the Golgi into the nucleus, thereby maintaining cell homeostasis; moreover, PERK and IRE1 activation contribute to LSDV replication. Our findings suggest that targeting UPR elements may be applied in response to infection from LSDV or even other poxviruses, such as monkeypox.

Keywords: cell signaling; endoplasmic reticulum stress; lumpy skin disease virus; poxvirus; unfolded protein response

DOI: https://doi.org/10.1096/fj.202300028R

J Cell Biol. 2023 May 01. pii: e202208147. [Epub ahead of print]222(5):

PERK prevents rhodopsin degradation during retinitis pigmentosa by inhibiting IRE1-induced autophagy.

Ning Zhao, Ning Li, Tao Wang.

Chronic endoplasmic reticulum (ER) stress is the underlying cause of many degenerative diseases, including autosomal dominant retinitis pigmentosa (adRP). In adRP, mutant rhodopsins accumulate and cause ER stress. This destabilizes wild-type rhodopsin and triggers photoreceptor cell degeneration. To reveal the mechanisms by which these mutant rhodopsins exert their dominant-negative effects, we established an in vivo fluorescence reporter system to monitor mutant and wild-type rhodopsin in Drosophila. By performing a genome-wide genetic screen, we found that PERK signaling plays a key role in maintaining rhodopsin homeostasis by attenuating IRE1 activities. Degradation of wild-type rhodopsin is mediated by selective autophagy of ER, which is induced by uncontrolled IRE1/XBP1 signaling and insufficient proteasome activities. Moreover, upregulation of PERK signaling prevents autophagy and suppresses retinal degeneration in the adRP model. These findings establish a pathological role for autophagy in this neurodegenerative condition and indicate that promoting PERK activity could be used to treat ER stress-related neuropathies, including adRP.

DOI: https://doi.org/10.1083/jcb.202208147