All Articles

Enrico Bracco^2*, Cristina Panuzzo¹, Barbara Pergolizzi^1*

¹Dept. of Clinical & Biological Sciences, University of Turin, Italy

²Dept. of Oncology, University of Turin, Italy

HECT ubiquitin ligases are key components of the eukaryotic ubiquitin-proteasome system controlling different cellular physiological aspects as well as the genesis of several human diseases. Among the HECT family, the HERC subfamily members are characterized by having one or more RCC1-like domains, a C-terminal HECT domain and the molecular mass ranging approximately from 120 kDa to 500 kDa. Due to their large size, some of them are refractory to functional characterization. We have recently identified and functionally characterized a novel large HECT member in Dictyostelium discoideum that, in many aspects, exhibits structural similarities with the mammalian large HERC1. In the present minireview, we shortly summarize and revise the current phylogenetic history of HERC proteins among the different living organisms.

Manuela M Almo¹, Isabel G Sousa², Andréa Q Maranhão^2,3, Marcelo M Brigido^2,3*

¹Molecular Pathology Graduation Program, Medicine Faculty, University of Brasilia, Brasilia, Brazil

²Department of Cell Biology, Institute of Biological Sciences, University of Brasilia, Brasilia, Brazil

³Institute for Immunology Investigation, a National Institute of Science and Technology

Long noncoding RNAs (lncRNAs) are regulatory RNA molecules that are involved in various biological processes. In the immune system, the lncRNAs play important roles in development, differentiation, survival, cell fate determination, proliferation and activation of immune cells. Lymphocytes are the main players of the adaptive immunity and CD3+ T cells acts as a master regulator for the immune responses. These cells following activation by antigens and co-stimulatory signals are differentiated into various effector T cell subsets, including CD4 and CD8 T cells. These heterogeneous populations can be distinguished based on molecular surface markers and subsets of these markers can be used to denote various stages of T lymphocyte differentiation, notwithstanding the CD3⁺ T cells phenotypes are markedly influenced by lncRNAs. In the present review, we summarize recent research on the role of long noncoding RNAs in subtypes of CD4⁺ and CD8⁺ human T cells.

Marek Adamowicz^1*

¹Genome Damage and Stability Centre, School of Life Sciences, University of Sussex, Falmer, Brighton BN1 9RH, UK.

ATM kinase is a master regulator of the DNA damage response (DDR). A recently published report from the d’Adda di Fagagna laboratory¹ sheds a light onto our understanding of ATM activation. In this short-commentary we will expand on this and other work to perceive better some of the aspects of ATM regulation.

Nicholas L. Cianciola^a,d and Cathleen R. Carlin^a,b,*

^aDepartments of Molecular Biology and Microbiology, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106

^bThe Case Comprehensive Cancer Center, School of Medicine, Case Western Reserve University, Cleveland, Ohio 44106

^dThe Lockwood Group, Stamford, CT 06901

The interplay between viruses and host factors regulating inflammatory or cytotoxic responses directed against infected cells is well documented. Viruses have evolved a wide array of mechanisms that strike a balance between the elimination of virus and immune-mediated tissue injury by antiviral immune responses. The topic of this mini-review is a series of recent studies demonstrating a link between cholesterol trafficking and innate immune responses in cells infected with human adenoviruses that provide the backbone of commonly used vectors in gene medicine. Besides revealing an unexpected role for lipid metabolism in immune evasion, these studies have important implications for understanding the molecular basis of cholesterol trafficking in normal cells and various disease states. They also describe a previously unappreciated host-virus interaction that may be employed by other pathogens to interfere with the host innate immune system.

Sarah Alter¹, Peter R. Rhode¹, Emily K. Jeng¹, and Hing C. Wong^1*

¹Altor BioScience, Miramar, Florida

This mini review provides an overview and rationale for creating IL-15-based fusion protein complexes to be used as targeted immunotherapeutic agents. IL-15 stimulates proliferation and activation of CD8+ T and natural killer cells which result in augmentation of their anti-tumor activities. We have created ALT-803, an IL-15 superagonist complex which exhibits longer serum half-life, longer retention in lymphoid tissues, and better immunostimulatory and anti-tumor activities compared to native IL-15. When used alone or in combination with other immunotherapeutic molecules in various mouse tumor models, ALT-803 effectively reduces tumor burden and prolongs survival by stimulating the innate and adaptive arms of the immune system. To evaluate whether ALT-803 could be used as a protein scaffold to create IL-15-based tumor cell-specific molecules, we genetically fused it with a single chain anti-CD20 antibody derived from the variable regions of rituximab. This novel fusion protein exhibits enhanced anti-tumor activity compared to rituximab while maintaining IL-15 immunostimulating properties. Thus, ALT-803 may be exploited as a versatile scaffold to produce multivalent targeted fusion proteins to improve the anti-tumor efficacy of other therapeutic agents in the clinic.

Laura Pulze¹, Miriam Capri², Annalisa Grimaldi¹, Stefano Salvioli², Gianluca Tettamanti¹, Magda de Eguileor^1*

¹University of Insubria, Department of Biotechnology and Life Sciences, 21100 Varese, Italy

²University of Bologna, Department of Experimental, Diagnostic and Specialty Medicine (DIMES), 40126 Bologna, Italy

W. Jean Dodds^1*

¹Hemopet, 938 Stanford Street, Santa Monica, California 90403, USA

Tuan Vo-Dinh*¹, Yang Liu¹, Bridget M Crawford¹, Hsin-Neng Wang¹, Hsiangkuo Yuan¹, Janna K Register¹, Christopher G Khoury¹

¹Fitzpatrick Institute for Photonics, Department of Biomedical Engineering, Department of Chemistry, Duke University, Durham, NC 27708-0281, USA

Cancer has been a significant threat to human health with more than eight million deaths each year in the world. There is an urgent need to develop novel methods to improve cancer management. Biocompatible gold nanostars (GNS) with tip-enhanced electromagnetic and optical properties have been developed and applied for multifunctional cancer diagnostics and therapy (theranostics). The GNS platform can be used for multiple sensing, imaging and treatment modalities, such as surface-enhanced Raman scattering, two-photon photoluminescence, magnetic resonance imaging and computed tomography as well as photothermal therapy and immunotherapy. GNS-mediated photothermal therapy combined with checkpoint immunotherapy has been found to reverse tumor-mediated immunosuppression, leading to the treatment of not only primary tumors but also cancer metastasis as well as inducing effective long-lasting immunity, i.e. an anticancer ‘vaccine’ effect.

Kao-Pin Hwang^1*, Ting-Yu Yen¹

Bettina Sehnert^1*, Harald Burkhardt², Stefan Dübel³, Reinhard E. Voll¹

The activation of intracellular signaling pathways such as the classical nuclear factor kappaB (NF-kappaB) pathway is related to the pathogenesis of several inflammatory autoimmune diseases including rheumatoid arthritis (RA). To clarify the role of disease-relevant cell-types and signaling molecules in vitro or in vivo, it is necessary to target them selectively without disturbing the homeostasis of the immune system. We developed sneaking ligand fusion proteins (SLFPs) for cell-type specific modulation of signaling pathways. We designed the first SLFPs to inhibit the activation of NF-kappaB, a key regulator of inflammation, solely in the activated endothelium. Our “sneaking ligand” NF-kappaB inhibitor (named SLC1) inhibits NF-kappaB activation specifically in E-selectin expressing cells in vitro and in mouse models of arthritis indicating the importance of NF-kappaB in the activated endothelium. Clinical signs of arthritis were ameliorated by SLC1 treatment. We conclude that the SLFP architecture consisting of easily exchangeable domains represents an attractive approach to utilize other disease-relevant biological targets both on the cell surface and intracellularly. By relying on two independent disease specific targets, SLFPs may increase the therapeutic efficacy and reduce adverse effects.

Asylkhan Rakhymzhan^1*, Randall L. Lindquist^1*, Anja E. Hauser^1,2#, Raluca Niesner^1#

In the last two decades intravital multi-photon imaging has become a central tool to investigate cellular and molecular dynamics of immune reactions in vivo. Currently, challenges in exploiting the full power of this technology include limitations on the number of simultaneously detectable parameters as well as in expanding the acquisition in time and space. Here we discuss technological advancements developed in order to overcome these challenges and focus on the example of germinal center reactions as multi-parametric immunological processes evolving over a time course of days and weeks.

Millet Treinin*

The nicotinic acetylcholine receptor (nAChR) gene family encodes for subunits of acetylcholine gated ion channels. These receptors are expressed widely and have many functions including anti-inflammatory effects mediated by the α7 nAChR, as part of the cholinergic anti-inflammatory pathway, in immune cells, microglia and astrocytes. Maturation of α7 nAChRs into functional ligand-gated ion channels in the plasma membrane is a complex process likely to require the RIC-3 protein. This endoplasmic reticulum resident chaperone affects maturation of multiple nAChRs, but its interaction with these receptors and its effects on their maturation differ for different nAChRs. Moreover, these interactions and effects are regulated by multiple mechanisms. Genetic analysis has implicated RIC-3 in the neuroinflammatory disease Multiple Sclerosis (MS), and in the neurodegenerative Parkinson's disease (PD). Neuroinflammation contributes to the progression of neurodegenerative diseases including PD. This information combines to suggest that RIC-3 may contribute to progression of both MS and PD via its effects on the α7 nAChR and the cholinergic anti-inflammatory pathway. Furthermore, we suggest that mechanisms regulating RIC-3 expression and activity may have a role in controlling inflammation.

Julie D. Saba*

After undergoing positive and negative selection in the thymus, surviving mature T cells egress from the thymic parenchyma and enter the bloodstream to participate in adaptive immunity. Thymic egress requires signals mediated by sphingosine-1-phosphate (S1P), a bioactive lipid that serves as the ligand for a family of G protein-coupled receptors (S1P1-5) expressed on many cell types, including T cells. In the final stage of their development, T cells upregulate S1P1 expression on the cell surface, which enables them to recognize and respond to a chemotactic S1P gradient that lures them into the bloodstream. The gradient is generated by an S1P source close to the site of egress combined with an S1P sink generated by the actions of S1P catabolic enzymes including S1P lyase (SPL), the only enzyme that irreversibly degrades S1P. The requisite contribution of SPL to thymic egress is demonstrated by the profound lymphopenia observed in SPL knockout (KO) mice and wild type mice treated with SPL inhibitors. SPL is robustly expressed in thymic epithelial cells (TECs), which make up the stromal reticular network of the thymus. However, TEC SPL was recently found to be dispensable for thymic egress. In contrast, deletion of SPL in dendritic cells (DCs) — which represent only a small percent of thymic stroma — disrupts the S1P gradient and blocks thymic egress. These recent observations identify DCs as homeostatic regulators of thymic export through the actions of SPL, thereby adding one more piece to the complex puzzle of how S1P signaling contributes to the regulation of T cell trafficking.

Quanquan Ding, Min Liu, Xiao-Lian Zhang*