&lt;b&gt;Iron deficiency induces autophagy and activates Nrf2 signal through modulating &lt;/b&gt;&lt;b&gt;p62/SQSTM &lt;/b&gt;

Inoue, Hirofumi; Hanawa, Nobuaki; Katsumata, Seishi; Katsumata-Tsuboi, Rie; Takahashi, Nobuyuki; Uehara, Mariko

doi:10.2220/biomedres.38.343

Cited by 24 publications

(14 citation statements)

References 33 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…; Inoue et al . ). Taken together, these results indicate that the accumulation of p62 protein is probably because of the autophagosome‐lysosome fusion deficiency that leads to prevention of p62 degradation.…”

Section: Resultsmentioning

confidence: 97%

Iron promotes α‐synuclein aggregation and transmission by inhibiting TFEB‐mediated autophagosome‐lysosome fusion

Xiao

Chen

Huang

et al. 2018

Journal of Neurochemistry

View full text Add to dashboard Cite

Recent studies have strongly shown that cell-to-cell transmission of neuropathogenic proteins is a common mechanism for the development of neurodegenerative diseases. However, the underlying cause is complex and little is known. Although distinct processes are involved in the pathogenesis of various diseases, they all share the common feature of iron accumulation, an attribute that is particularly prominent in synucleinopathies. However, whether iron is a cofactor in facilitating the spread of α-synuclein remains unclear. Here, we constructed a cell-to-cell transmission model of α-synuclein using SN4741 cell line based on adenovirus vectors. Cells were treated with FeCl and α-synuclein aggregation and transmission were then evaluated. In addition, the possible mechanisms were investigated through gene knockdown or over-expression. Our results demonstrated that iron promoted α-synuclein aggregation and transmission by inhibiting autophagosome-lysosome fusion. Furthermore, iron decreased the expression of nuclear transcription factor EB (TFEB), a master transcriptional regulator of autophagosome-lysosome fusion, and inhibited its nuclear translocation through activating AKT/mTORC1 signaling. After silencing TFEB, ratios of α-synuclein aggregation and transmission were not significantly altered by the presence of iron; on the other hand, when TFEB was over-expressed, the transmission of α-synuclein induced by iron was obviously reversed; suggesting the mechanism by which iron promotes α-synuclein transmission may be mediated by TFEB. Taken together, our data reveal a previously unknown relationship between iron and α-synuclein, and identify TFEB as not only a potential target for preventing α-synuclein transmission, but also a critical factor for iron-induced α-synuclein aggregation and transmission. Indeed, this newly discovered role of iron and TFEB in synucleinopathies may provide novel targets for developing therapeutic strategies to prevent α-synuclein transmission in Parkinson's disease.

show abstract

Section: Resultsmentioning

confidence: 97%

Iron promotes α‐synuclein aggregation and transmission by inhibiting TFEB‐mediated autophagosome‐lysosome fusion

Xiao

Chen

Huang

et al. 2018

Journal of Neurochemistry

View full text Add to dashboard Cite

show abstract

“…The SQSTM1 gene promoter indeed contains specific response elements including kB, CLEAR, and ARE, which respond to the respective master gene regulators NF-kB, Mit/TFE, and Nrf2. Specifically, NF-kB can activate p62 under inflammatory or pro-survival responses, Mit/TFE and Nrf2 stimulate p62 expression under metabolic stress and oxidative stress, respectively [ 24 , 25 , 26 ].…”

Section: P62 Structure Post-translational Modifications and Confmentioning

confidence: 99%

p62: Friend or Foe? Evidences for OncoJanus and NeuroJanus Roles

Emanuele

Lauricella

D’Anneo

et al. 2020

IJMS

View full text Add to dashboard Cite

p62 is a versatile protein involved in the delicate balance between cell death and survival, which is fundamental for cell fate decision in the context of both cancer and neurodegenerative diseases. As an autophagy adaptor, p62 recognizes polyubiquitin chains and interacts with LC3, thereby targeting the selected cargo to the autophagosome with consequent autophagic degradation. Beside this function, p62 behaves as an interactive hub in multiple signalling including those mediated by Nrf2, NF-κB, caspase-8, and mTORC1. The protein is thus crucial for the control of oxidative stress, inflammation and cell survival, apoptosis, and metabolic reprogramming, respectively. As a multifunctional protein, p62 falls into the category of those factors that can exert opposite roles in the cells. Chronic p62 accumulation was found in many types of tumors as well as in stress granules present in different forms of neurodegenerative diseases. However, the protein seems to have a Janus behaviour since it may also serve protective functions against tumorigenesis or neurodegeneration. This review describes the diversified roles of p62 through its multiple domains and interactors and specifically focuses on its oncoJanus and neuroJanus roles.

show abstract

“…However, downregulation of PRMTs and protein methylation in iron-deficient condition has not yet been clearly understood. Interestingly, our group reported that iron deficiency induced ROS production [ 26 ]. To the best of our knowledge, this is the novel discovery that showed that protein methylation and expression of PRMTs during iron-deficient conditions are negatively regulated in vitro and in vivo .…”

Section: Discussionmentioning

confidence: 99%

Iron deficiency negatively regulates protein methylation via the downregulation of protein arginine methyltransferase

Inoue

Hanawa

Katsumata

et al. 2020

Heliyon

Self Cite

View full text Add to dashboard Cite

Iron is an essential trace metal for all biological processes and plays a role in almost every aspect of body growth. Previously, we found that iron-depletion downregulated the expression of proteins, arginine methyltransferase-1 and 3 (PRMT1 and PRMT3), by an iron-specific chelator, deferoxamine (DFO), in rat liver FAO cell line using DNA microarray analysis (unpublished data). However, regulatory mechanisms underlying the association between iron deficiency and PRMT expression are unclear in vitro and in vivo . In the present study, we revealed that the treatment of cells with two iron-specific chelators, DFO and deferasirox (DFX), downregulated the gene and protein expression of PRMT1 and 3 as compared with the untreated cells. Subsequently, DFO and DFX treatments decreased protein methylation. Importantly, these effects were attenuated by a holo-transferrin treatment. Furthermore, weanling Wistar-strain rats were fed a control diet or an iron-deficient diet for 4 weeks. Dietary iron deficiency was found to decrease the concentration of hemoglobin and liver iron while increasing the heart weight. PRMT and protein methylation levels were also significantly reduced in the iron-deficient group as compared to the control group. To our knowledge, this is the first study to demonstrate that PRMT levels and protein methylation are reduced in iron-deficient models, in vitro and in vivo .

show abstract

<b>Iron deficiency induces autophagy and activates Nrf2 signal through modulating </b><b>p62/SQSTM </b>

Cited by 24 publications

References 33 publications

Iron promotes α‐synuclein aggregation and transmission by inhibiting TFEB‐mediated autophagosome‐lysosome fusion

Iron promotes α‐synuclein aggregation and transmission by inhibiting TFEB‐mediated autophagosome‐lysosome fusion

p62: Friend or Foe? Evidences for OncoJanus and NeuroJanus Roles

Iron deficiency negatively regulates protein methylation via the downregulation of protein arginine methyltransferase

Contact Info

Product

Resources

About