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Biomedicines
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Advanced Research on Molecular Chaperones
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Advanced Research on Molecular Chaperones

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Cell Biology and Pathology".

Deadline for manuscript submissions: closed (30 September 2022) | Viewed by 11908

Special Issue Editor

Prof. Dr. Salvatore Vincent Pizzo

E-Mail Website
Guest Editor
Department of Pathology, Duke University Medical Center, Durham, NC 27710, USA
Interests: intracellular proteins; cell surface; signaling receptors; expression; GRP 78; cancer cell proliferation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The intracellular chaperone GRP 78 was first identified as a cell surface signaling receptor in 2001 (reference 301 from CV) This was a surprising observation, but hundreds of subsequent publications have confirmed that cancer cell surface GRP 78 functions as a cell surface receptor regulation pro-proliferative, pro-migratory, and anti-apoptotic signaling cascades. Autoantibodies to the amino-terminal domain of GRP 78 may occur in the plasma of cancer patients. This is a harbinger of a poor prognosis asthese antibodies are receptor agonists. However, antibodies to the carboxyl-terminal domain can be produced in mice and these antibodies are receptor antagonists. Humanized versions of these antibodies have therapeutic potential in the treatment of cancer. Many subsequent studies demonstrate that ligation of cell surface GRP 78 regulates cancer cell metabolism. This Special Issue is intended to explore the role of cell surface GRP 78 in transcriptional regulation of cancer cells. This is a promising area of exploration which may lead to improved cancer therapy. We invite potential authors to submit an article to this Special Issue of biomedicines.

While GRP 78 has been the best studied chaperone identified on the cell surface, it is not the only member of this group of proteins to occur on the cell surface. For example, HL 60 also occurs on the cell surface of various types of cells. This Special Issue of Biomedicines welcomes work involving the role of other chaperones as cell surface proteins which exhibit new functions as regulators of cell function.

Prof. Dr. Salvatore Vincent Pizzo
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

  • GRP 78
  • cell surface GRP 78
  • transcriptional regulation
  • cancer cell metabolism
  • molecular chaperones

Published Papers (5 papers)

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Research

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10 pages, 1494 KiB  
Communication
Impaired Heat Shock Protein Expression in Activated T Cells in B-Cell Lymphoma
by Zarema Albakova, Yana Mangasarova and Alexander Sapozhnikov
Biomedicines 2022, 10(11), 2747; https://doi.org/10.3390/biomedicines10112747 - 28 Oct 2022
Cited by 2 | Viewed by 1522
Abstract
Heat shock proteins (HSPs) are molecular chaperones that act in a variety of cellular processes, ensuring protein homeostasis and integrity. HSPs play critical roles in the modulation of various immune cells. However, the role of HSPs in T cell activation is largely unknown. [...] Read more.
Heat shock proteins (HSPs) are molecular chaperones that act in a variety of cellular processes, ensuring protein homeostasis and integrity. HSPs play critical roles in the modulation of various immune cells. However, the role of HSPs in T cell activation is largely unknown. We show that HSPs are upregulated following CD3/CD28 stimulation, suggesting that HSP expression might be regulated via TCR. We found that B-cell lymphoma (BCL) patients have dysregulated expression of intracellular and extracellular HSPs, immune checkpoints PD-1, CTLA-4, and STAT3 in CD3/CD28-activated T cells. Consistent with previous findings, we show that HSP90 inhibition downregulated CD4 and CD8 surface markers in healthy controls and BCL patients. HSP90 inhibition alone or in combination with PD-1 or CTLA-4 inhibitors differentially affected CD4+ and CD8+ T cell degranulation responses when stimulated with allogeneic DCs or CD3/CD28 in BCL patients. Additionally, we showed that HSP90 inhibition does not significantly affect intracellular PD-1 and CTLA-4 expression in CD3/CD28-activated T cells. These findings may provide the basis for the discovery of novel immunological targets for the treatment of cancer patients and improve our understanding of HSP functions in immune cells. Full article
(This article belongs to the Special Issue Advanced Research on Molecular Chaperones)
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17 pages, 2008 KiB  
Article
Integrin β1/Cell Surface GRP78 Complex Regulates TGFβ1 and Its Profibrotic Effects in Response to High Glucose
by Jackie Trink, Renzhong Li, Evan Squire, Kian O’Neil, Phoebe Zheng, Bo Gao and Joan C. Krepinsky
Biomedicines 2022, 10(9), 2247; https://doi.org/10.3390/biomedicines10092247 - 10 Sep 2022
Cited by 2 | Viewed by 1525
Abstract
Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Characterized by overproduction and accumulation of extracellular matrix (ECM) proteins, glomerular sclerosis is its earliest manifestation. High glucose (HG) plays a central role by increasing matrix production by glomerular mesangial cells [...] Read more.
Diabetic kidney disease (DKD) is the leading cause of kidney failure worldwide. Characterized by overproduction and accumulation of extracellular matrix (ECM) proteins, glomerular sclerosis is its earliest manifestation. High glucose (HG) plays a central role by increasing matrix production by glomerular mesangial cells (MC). We previously showed that HG induces translocation of GRP78 from the endoplasmic reticulum to the cell surface (csGRP78), where it acts as a signaling molecule to promote intracellular profibrotic FAK/Akt activation. Here, we identify integrin β1 as a key transmembrane signaling partner for csGRP78. We show that it is required for csGRP78-regulated FAK/Akt activation in response to HG, as well as downstream production, secretion and activity of the well characterized profibrotic cytokine transforming growth factor β1 (TGFβ1). Intriguingly, integrin β1 also itself promotes csGRP78 translocation. Furthermore, integrin β1 effects on cytoskeletal organization are not required for its function in csGRP78 translocation and signaling. These data together support an important pathologic role for csGRP78/integrin β1 in mediating key profibrotic responses to HG in kidney cells. Inhibition of their interaction will be further evaluated as a therapeutic target to limit fibrosis progression in DKD. Full article
(This article belongs to the Special Issue Advanced Research on Molecular Chaperones)
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Review

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15 pages, 4963 KiB  
Review
GRP78, a Novel Host Factor for SARS-CoV-2: The Emerging Roles in COVID-19 Related to Metabolic Risk Factors
by Jihoon Shin, Shinichiro Toyoda, Atsunori Fukuhara and Iichiro Shimomura
Biomedicines 2022, 10(8), 1995; https://doi.org/10.3390/biomedicines10081995 - 17 Aug 2022
Cited by 9 | Viewed by 2051
Abstract
The outbreak of coronavirus disease 19 (COVID-19), caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in an unprecedented amount of infection cases and deaths, leading to the global health crisis. Despite many research efforts, our understanding of [...] Read more.
The outbreak of coronavirus disease 19 (COVID-19), caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has resulted in an unprecedented amount of infection cases and deaths, leading to the global health crisis. Despite many research efforts, our understanding of COVID-19 remains elusive. Recent studies have suggested that cell surface glucose-regulated protein 78 (GRP78) acts as a host co-receptor for SARS-CoV-2 infection and is related to COVID-19 risks, such as older age, obesity, and diabetes. Given its significance in a wide range of biological processes, such as protein homeostasis and cellular signaling, GRP78 might also play an important role in various stages of the viral life cycle and pathology of SARS-CoV-2. In this perspective, we explore the emerging and potential roles of GRP78 in SARS-CoV-2 infection. Additionally, we discuss the association with COVID-19 risks and symptoms. We hope this review article will be helpful to understand COVID-19 pathology and promote attention and study of GRP78 from many clinical and basic research fields. Full article
(This article belongs to the Special Issue Advanced Research on Molecular Chaperones)
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13 pages, 1173 KiB  
Review
Physiological Roles of the Autoantibodies to the 78-Kilodalton Glucose-Regulated Protein (GRP78) in Cancer and Autoimmune Diseases
by Mario Gonzalez-Gronow and Salvatore Vincent Pizzo
Biomedicines 2022, 10(6), 1222; https://doi.org/10.3390/biomedicines10061222 - 24 May 2022
Cited by 7 | Viewed by 2977
Abstract
The 78 kDa glucose-regulated protein (GRP78), a member of the 70 kDa heat-shock family of molecular chaperones (HSP70), is essential for the regulation of the unfolded protein response (UPR) resulting from cellular endoplasmic reticulum (ER) stress. During ER stress, GRP78 evades retention mechanisms [...] Read more.
The 78 kDa glucose-regulated protein (GRP78), a member of the 70 kDa heat-shock family of molecular chaperones (HSP70), is essential for the regulation of the unfolded protein response (UPR) resulting from cellular endoplasmic reticulum (ER) stress. During ER stress, GRP78 evades retention mechanisms and is translocated to the cell surface (csGRP78) where it functions as an autoantigen. Autoantibodies to GRP78 appear in prostate, ovarian, gastric, malignant melanoma, and colorectal cancers. They are also found in autoimmune pathologies such as rheumatoid arthritis (RA), neuromyelitis optica (NMO), anti-myelin oligodendrocyte glycoprotein antibody-associated disorder (AMOGAD), Lambert-Eaton myasthenic syndrome (LEMS), multiple sclerosis (MS), neuropsychiatric systemic lupus erythematosus (NPSLE) and type 1 diabetes (T1D). In NMO, MS, and NPSLE these autoantibodies disrupt and move across the blood-brain barrier (BBB), facilitating their entry and that of other pathogenic antibodies to the brain. Although csGRP78 is common in both cancer and autoimmune diseases, there are major differences in the specificity of its autoantibodies. Here, we discuss how ER mechanisms modulate csGRP78 antigenicity and the production of autoantibodies, permitting this chaperone to function as a dual compartmentalized receptor with independent signaling pathways that promote either pro-proliferative or apoptotic signaling, depending on whether the autoantibodies bind csGRP78 N- or C-terminal regions. Full article
(This article belongs to the Special Issue Advanced Research on Molecular Chaperones)
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Graphical abstract

13 pages, 1372 KiB  
Review
Scratching the Surface—An Overview of the Roles of Cell Surface GRP78 in Cancer
by Jack Chen, Edward G. Lynn, Tamana R. Yousof, Hitesh Sharma, Melissa E. MacDonald, Jae Hyun Byun, Bobby Shayegan and Richard C. Austin
Biomedicines 2022, 10(5), 1098; https://doi.org/10.3390/biomedicines10051098 - 10 May 2022
Cited by 7 | Viewed by 2856
Abstract
The 78 kDa glucose-regulated protein (GRP78) is considered an endoplasmic reticulum (ER)-resident molecular chaperone that plays a crucial role in protein folding homeostasis by regulating the unfolded protein response (UPR) and inducing numerous proapoptotic and autophagic pathways within the eukaryotic cell. However, in [...] Read more.
The 78 kDa glucose-regulated protein (GRP78) is considered an endoplasmic reticulum (ER)-resident molecular chaperone that plays a crucial role in protein folding homeostasis by regulating the unfolded protein response (UPR) and inducing numerous proapoptotic and autophagic pathways within the eukaryotic cell. However, in cancer cells, GRP78 has also been shown to migrate from the ER lumen to the cell surface, playing a role in several cellular pathways that promote tumor growth and cancer cell progression. There is another insidious consequence elicited by cell surface GRP78 (csGRP78) on cancer cells: the accumulation of csGRP78 represents a novel neoantigen leading to the production of anti-GRP78 autoantibodies that can bind csGRP78 and further amplify these cellular pathways to enhance cell growth and mitigate apoptotic cell death. This review examines the current body of literature that delineates the mechanisms by which ER-resident GRP78 localizes to the cell surface and its consequences, as well as potential therapeutics that target csGRP78 and block its interaction with anti-GRP78 autoantibodies, thereby inhibiting further amplification of cancer cell progression. Full article
(This article belongs to the Special Issue Advanced Research on Molecular Chaperones)
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