Regulation of Protein Quality Control by UBE4B and LSD1 through p53-Mediated Transcription

Periz, Goran; Lu, Jun; Zhang, Tao; Kankel, Mark W.; Jablonski, Angela M.; Kalb, Robert G.; McCampbell, Alexander; Wang, Jiou

doi:10.1371/journal.pbio.1002114

“…Decreased aggregation of the human SOD1(G85R) protein has been shown to correlate with improved protein quality control in C . elegans neurons [72–74]. As reported previously [73, 75], expression of SOD1(G85R)::YFP resulted in the formation of aggregates of heterogeneous sizes with large and small aggregates in body wall muscle and ASI neurons, respectively (S5C Fig).…”

Section: Resultssupporting

confidence: 73%

Structural and Functional Recovery of Sensory Cilia in C. elegans IFT Mutants upon Aging

Cornils

¹

,

Maurya

²

,

Tereshko

³

et al. 2016

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The majority of cilia are formed and maintained by the highly conserved process of intraflagellar transport (IFT). Mutations in IFT genes lead to ciliary structural defects and systemic disorders termed ciliopathies. Here we show that the severely truncated sensory cilia of hypomorphic IFT mutants in C. elegans transiently elongate during a discrete period of adult aging leading to markedly improved sensory behaviors. Age-dependent restoration of cilia morphology occurs in structurally diverse cilia types and requires IFT. We demonstrate that while DAF-16/FOXO is dispensable, the age-dependent suppression of cilia phenotypes in IFT mutants requires cell-autonomous functions of the HSF1 heat shock factor and the Hsp90 chaperone. Our results describe an unexpected role of early aging and protein quality control mechanisms in suppressing ciliary phenotypes of IFT mutants, and suggest possible strategies for targeting subsets of ciliopathies.

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“…Decreased aggregation of the human SOD1(G85R) protein has been shown to correlate with improved protein quality control in C. elegans neurons [72][73][74]. As reported previously [73,75], expression of SOD1 (G85R)::YFP resulted in the formation of aggregates of heterogeneous sizes with large and small aggregates in body wall muscle and ASI neurons, respectively (S5C Fig). While aggregates in muscle did not appear to be grossly affected by age or genetic background, the number of small aggregates in ASI decreased in both 4d old wild-type and osm-6 animals (S5D Fig). This reduction in aggregate number was not correlated with reduced ASI promoter activity in aged animals (S5E Fig). These results suggest that improved proteostasis may contribute to AdCR.…”

Section: Improved Proteostasis Mechanisms May Be Necessary For Adcrsupporting

confidence: 74%

Structural and Functional Recovery of Sensory Cilia in C. elegans IFT Mutants upon Aging

Maurya

¹

,

Cornils

²

,

Tereshko

³

et al. 2017

Mechanisms of Development

0

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The majority of cilia are formed and maintained by the highly conserved process of intraflagellar transport (IFT). Mutations in IFT genes lead to ciliary structural defects and systemic disorders termed ciliopathies. Here we show that the severely truncated sensory cilia of hypomorphic IFT mutants in C. elegans transiently elongate during a discrete period of adult aging leading to markedly improved sensory behaviors. Age-dependent restoration of cilia morphology occurs in structurally diverse cilia types and requires IFT. We demonstrate that while DAF-16/FOXO is dispensable, the age-dependent suppression of cilia phenotypes in IFT mutants requires cell-autonomous functions of the HSF1 heat shock factor and the Hsp90 chaperone. Our results describe an unexpected role of early aging and protein quality control mechanisms in suppressing ciliary phenotypes of IFT mutants, and suggest possible strategies for targeting subsets of ciliopathies. Author SummaryCilia are 'antenna-like' structures that are present on nearly all cell types in animals. These structures are important for sensing and signaling external cues to the cell. Most cilia are formed by a protein transport process called 'intraflagellar transport' or IFT. Mutations in IFT genes result in severe cilia defects, and are causal to a large number of diverse human disorders called ciliopathies. Since the genes and processes by which cilia are formed are similar across species, studies in experimental models such as the nematode C. elegans can greatly inform our overall understanding of cilia formation and function. Here we report the surprising observation that the structures and functions of severely defective cilia in nematodes with disrupted IFT genes markedly improve upon aging. We find that protein quality control mechanisms that normally decline in aging are required for this age-dependent recovery of cilia structure. Our results raise the possibility that the effects of some mutations in IFT genes can be bypassed under specific conditions, thereby restoring cilia functions.

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“…events ( 130,131 ), further functional studies are required for validation in cancer models in vivo .…”

Section: Reviewmentioning

confidence: 99%

Endoplasmic Reticulum Stress–Activated Cell Reprogramming in Oncogenesis

Chevet

¹

,

Hetz

²

,

Samali

³

2015

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Stress induced by the accumulation of unfolded proteins in the endoplasmic reticulum (ER) is observed in many human diseases, including cancers. Cellular adaptation to ER stress is mediated by the unfolded protein response (UPR), which aims at restoring ER homeostasis. The UPR has emerged as a major pathway in remodeling cancer gene expression, thereby either preventing cell transformation or providing an advantage to transformed cells. UPR sensors are highly regulated by the formation of dynamic protein scaffolds, leading to integrated reprogramming of the cells. Herein, we describe the regulatory mechanisms underlying UPR signaling upon cell intrinsic or extrinsic challenges, and how they engage cell transformation programs and/or provide advantages to cancer cells, leading to enhanced aggressiveness or chemoresistance. We discuss the emerging crosstalk between the UPR and related metabolic processes to ensure maintenance of protein homeostasis and its impact on cell transformation and tumor growth.Signifi cance: ER stress signaling is dysregulated in many forms of cancer and contributes to tumor growth as a survival factor, in addition to modulating other disease-associated processes, including cell migration, cell transformation, and angiogenesis. Evidence for targeting the ER stress signaling pathway as an anticancer strategy is compelling, and novel agents that selectively inhibit the UPR have demonstrated preliminary evidence of preclinical effi cacy with an acceptable safety profi le. Cancer Discov; 5(6);

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Regulation of Protein Quality Control by UBE4B and LSD1 through p53-Mediated Transcription

Cited by 44 publications

References 69 publications

Structural and Functional Recovery of Sensory Cilia in C. elegans IFT Mutants upon Aging

Structural and Functional Recovery of Sensory Cilia in C. elegans IFT Mutants upon Aging

Structural and Functional Recovery of Sensory Cilia in C. elegans IFT Mutants upon Aging

Endoplasmic Reticulum Stress–Activated Cell Reprogramming in Oncogenesis

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