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Biomedicines
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Regulatory Mechanisms of Protein Homeostasis: Implications for Therapeutics of Cancer...
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Regulatory Mechanisms of Protein Homeostasis: Implications for Therapeutics of Cancer and Neurological Disorders

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 3773

Special Issue Editor

Dr. Janakiram R. Vangala

E-Mail Website
Guest Editor
Department of Pathology and Massey Cancer Center, Virginia Commonwealth University, Richmond, VA 23298, USA
Interests: ubiquitin proteasome system; autophagy; cancer; neurological disorders; Nrf1(Nfe2l1); DDI2; NGly1; cell signaling; drug screening

Special Issue Information

Dear Colleagues,

Protein homeostasis is crucial for healthy survival, function and division of the cell. Timely degradation of transcription factors, signaling proteins, cell organelles, clearance of protein aggregates, abnormal, damaged and misfolded proteins are central part of protein homeostasis. The ubiquitin proteasome system (UPS), lysosome mediated autophagy pathways are key mechanistic components of protein homeostasis. Abnormal function of protein homeostasis leads to the stress and severe pathological conditions such as cancer, neurological disorders, heart associated conditions are associated with stress regulated cellular pathway modulation.

Understanding the regulatory mechanisms of protein homeostasis components is critical to design and develop therapeutics for the respective pathological conditions. Various ubiquitin, proteasome, and autophagy inhibitors had proven advantage in patients. This Special Issue of Biomedicines focuses on original manuscripts and reviews on regulatory mechanisms, and drug strategies targeting ubiquitin proteasome system and autophagy pathway.

Dr. Janakiram R. Vangala
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biomedicines is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2600 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • ubiquitin proteasome system
  • autophagy
  • cancer
  • neurological disorders
  • Nrf1(Nfe2l1)
  • DDI2
  • NGly1
  • cell signaling
  • drug screening

Published Papers (1 paper)

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Research

21 pages, 32383 KiB  
Article
STING-Triggered CNS Inflammation in Human Neurodegenerative Diseases
by Alex S. Ferecskó, Miranda J. Smallwood, Adrian Moore, Corin Liddle, Jia Newcombe, Janet Holley, Jacqueline Whatmore, Nicholas J. Gutowski and Paul Eggleton
Biomedicines 2023, 11(5), 1375; https://doi.org/10.3390/biomedicines11051375 - 5 May 2023
Cited by 8 | Viewed by 3554
Abstract
Background: Some neurodegenerative diseases have an element of neuroinflammation that is triggered by viral nucleic acids, resulting in the generation of type I interferons. In the cGAS-STING pathway, microbial and host-derived DNA bind and activate the DNA sensor cGAS, and the resulting cyclic [...] Read more.
Background: Some neurodegenerative diseases have an element of neuroinflammation that is triggered by viral nucleic acids, resulting in the generation of type I interferons. In the cGAS-STING pathway, microbial and host-derived DNA bind and activate the DNA sensor cGAS, and the resulting cyclic dinucleotide, 2′3-cGAMP, binds to a critical adaptor protein, stimulator of interferon genes (STING), which leads to activation of downstream pathway components. However, there is limited work demonstrating the activation of the cGAS-STING pathway in human neurodegenerative diseases. Methods: Post-mortem CNS tissue from donors with multiple sclerosis (n = 4), Alzheimer’s disease (n = 6), Parkinson’s disease (n = 3), amyotrophic lateral sclerosis (n = 3) and non-neurodegenerative controls (n = 11) were screened by immunohistochemistry for STING and relevant protein aggregates (e.g., amyloid-β, α-synuclein, TDP-43). Human brain endothelial cells were cultured and stimulated with the STING agonist palmitic acid (1–400 μM) and assessed for mitochondrial stress (release of mitochondrial DNA into cytosol, increased oxygen consumption), downstream regulator factors, TBK-1/pIRF3 and inflammatory biomarker interferon-β release and changes in ICAM-1 integrin expression. Results: In neurodegenerative brain diseases, elevated STING protein was observed mainly in brain endothelial cells and neurons, compared to non-neurodegenerative control tissues where STING protein staining was weaker. Interestingly, a higher STING presence was associated with toxic protein aggregates (e.g., in neurons). Similarly high STING protein levels were observed within acute demyelinating lesions in multiple sclerosis subjects. To understand non-microbial/metabolic stress activation of the cGAS-STING pathway, brain endothelial cells were treated with palmitic acid. This evoked mitochondrial respiratory stress up to a ~2.5-fold increase in cellular oxygen consumption. Palmitic acid induced a statistically significant increase in cytosolic DNA leakage from endothelial cell mitochondria (Mander’s coefficient; p < 0.05) and a significant increase in TBK-1, phosphorylated transcription factor IFN regulatory factor 3, cGAS and cell surface ICAM. In addition, a dose response in the secretion of interferon-β was observed, but it failed to reach statistical significance. Conclusions: The histological evidence shows that the common cGAS-STING pathway appears to be activated in endothelial and neural cells in all four neurodegenerative diseases examined. Together with the in vitro data, this suggests that the STING pathway might be activated via perturbation of mitochondrial stress and DNA leakage, resulting in downstream neuroinflammation; hence, this pathway may be a target for future STING therapeutics. Full article
(This article belongs to the Special Issue Regulatory Mechanisms of Protein Homeostasis: Implications for Therapeutics of Cancer and Neurological Disorders)
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