XBP-1 Is a Cell-Nonautonomous Regulator of Stress Resistance and Longevity

Taylor, Rebecca C.; Dillin, Andrew

doi:10.1016/j.cell.2013.05.042

Cited by 529 publications

(652 citation statements)

References 51 publications

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“…Our data are consistent with more recent evidence showing that XBP-1 can act cell nonautonomously in neuronal cells to influence the ER stress response in other tissues (37). Neuronal signaling pathways may regulate the UPR in the intestine to integrate this response into other functions of the organism (37,38).…”

Section: Hpl-2 Expression In Neuronal Cells Can Negatively Influencesupporting

confidence: 81%

The Caenorhabditis elegans HP1 family protein HPL-2 maintains ER homeostasis through the UPR and hormesis

Kozlowski

Garvis

Bedet

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Cellular adaptation to environmental changes and stress relies on a wide range of regulatory mechanisms that are tightly controlled at several levels, including transcription. Chromatin structure and chromatin binding proteins are important factors contributing to the transcriptional response to stress. However, it remains largely unknown to what extent specific chromatin factors influence the response to distinct forms of stress in a developmental context. One of the best characterized stress response pathways is the unfolded protein response (UPR), which is activated by accumulation of misfolded proteins in the endoplasmic reticulum (ER). Here, we show that Caenorhabditis elegans heterochromatin protein like-2 (HPL-2), the homolog of heterochromatin protein 1 (HP1), downregulates the UPR in the intestine. Inactivation of HPL-2 results in an enhanced resistance to ER stress dependent on the X-box binding protein 1 (XBP-1)/inositol requiring enzyme 1 branch of the UPR and the closely related process of autophagy. Increased resistance to ER stress in animals lacking HPL-2 is associated with increased basal levels of XBP-1 activation and ER chaperone expression under physiological conditions, which may in turn activate an adaptive response known as ER hormesis. HPL-2 expression in intestinal cells is sufficient to rescue stress resistance, whereas expression in neuronal cells negatively influenced the ER stress response through a cell-nonautonomous mechanism. We further show that the retinoblastoma protein homolog LIN-35 and the LIN-13 zinc finger protein act in the same pathway as HPL-2 to limit the ER stress response. Altogether, our results point to multiple functions for HP1 in different cell types to maintain ER homeostasis.

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Section: Hpl-2 Expression In Neuronal Cells Can Negatively Influencesupporting

confidence: 81%

The Caenorhabditis elegans HP1 family protein HPL-2 maintains ER homeostasis through the UPR and hormesis

Kozlowski

Garvis

Bedet

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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“…Evidence from C. elegans and Drosophila points to a connection between neuronal proteostasis and somatic aging (44,(53)(54)(55). Stress response and protein homeostasis maintenance in those organisms are orchestrated at least in part via cell nonautonomous neuronal control.…”

Section: Discussionmentioning

confidence: 99%

Exogenous Hsp70 delays senescence and improves cognitive function in aging mice

Бобкова

Евгеньев

Гарбуз

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

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Molecular chaperone Heat Shock Protein 70 (Hsp70) plays an important protective role in various neurodegenerative disorders often associated with aging, but its activity and availability in neuronal tissue decrease with age. Here we explored the effects of intranasal administration of exogenous recombinant human Hsp70 (eHsp70) on lifespan and neurological parameters in middle-aged and old mice. Long-term administration of eHsp70 significantly enhanced the lifespan of animals of different age groups. Behavioral assessment after 5 and 9 mo of chronic eHsp70 administration demonstrated improved learning and memory in old mice. Likewise, the investigation of locomotor and exploratory activities after eHsp70 treatment demonstrated a significant therapeutic effect of this chaperone. Measurements of synaptophysin show that eHsp70 treatment in old mice resulted in larger synaptophysin-immunopositive areas and higher neuron density compared with control animals. Furthermore, eHsp70 treatment decreased accumulation of lipofuscin, an aging-related marker, in the brain and enhanced proteasome activity. The potential of eHsp70 intranasal treatment to protect synaptic machinery in old animals offers a unique pharmacological approach for various neurodegenerative disorders associated with human aging.

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“…The expression of a constitutively active isoform of the transcription factor XBP (XBPs) in neurons activates the UPR ER in distal tissues (Taylor and Dillin 2013). Further evidence supporting the roles of neurons in the regulation of UPR ER was recently provided by the report that the overactivation of IRE1 in ASI neurons promotes apoptosis of the worm's germ cells (LeviFerber et al 2014), cells whose ablation confers proteostasis in muscle cells (Shemesh et al 2013).…”

Section: Protein Quality Control At the Organismal Levelmentioning

confidence: 97%

Protein Quality Control in Health and Disease

Dubnikov

Ben‐Gedalya

Cohen

2016

Cold Spring Harb Perspect Biol

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Maintaining functional protein homeostasis ( proteostasis) is a constant challenge in the face of limited protein-folding capacity, environmental threats, and aging. Cells have developed several quality-control mechanisms that assist nascent polypeptides to fold properly, clear misfolded molecules, respond to the accumulation of protein aggregates, and deposit potentially toxic conformers in designated sites. Proteostasis collapse can lead to the development of diseases known as proteinopathies. Here we delineate the current knowledge on the different layers of protein quality-control mechanisms at the organelle and cellular levels with an emphasis on the prion protein (PrP). We also describe how protein quality control is integrated at the organismal level and discuss future perspectives on utilizing proteostasis maintenance as a strategy to develop novel therapies for the treatment of proteinopathies.

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XBP-1 Is a Cell-Nonautonomous Regulator of Stress Resistance and Longevity

Cited by 529 publications

References 51 publications

The Caenorhabditis elegans HP1 family protein HPL-2 maintains ER homeostasis through the UPR and hormesis

The Caenorhabditis elegans HP1 family protein HPL-2 maintains ER homeostasis through the UPR and hormesis

Exogenous Hsp70 delays senescence and improves cognitive function in aging mice

Protein Quality Control in Health and Disease

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