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      Noncytotoxic functions of killer cell granzymes in viral infections

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          Abstract

          Cytotoxic lymphocytes produce granules armed with a set of 5 serine proteases (granzymes (Gzms)), which, together with the pore-forming protein (perforin), serve as a major defense against viral infections in humans. This granule-exocytosis pathway subsumes a well-established mechanism in which target cell death is induced upon perforin-mediated entry of Gzms and subsequent activation of various (apoptosis) pathways. In the past decade, however, a growing body of evidence demonstrated that Gzms also inhibit viral replication and potential reactivation in cell death–independent manners. For example, Gzms can induce proteolysis of viral or host cell proteins necessary for the viral entry, release, or intracellular trafficking, as well as augment pro-inflammatory antiviral cytokine response. In this review, we summarize current evidence for the noncytotoxic mechanisms and roles by which killer cells can use Gzms to combat viral infections, and we discuss the potential thereof for the development of novel therapies.

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          Most cited references135

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          Perforin and granzymes: function, dysfunction and human pathology.

          A defining property of cytotoxic lymphocytes is their expression and regulated secretion of potent toxins, including the pore-forming protein perforin and serine protease granzymes. Until recently, mechanisms of pore formation and granzyme transfer into the target cell were poorly understood, but advances in structural and cellular biology have now begun to unravel how synergy between perforin and granzymes brings about target cell death. These and other advances are demonstrating the surprisingly broad pathophysiological roles of the perforin–granzyme pathway, and this has important implications for understanding immune homeostasis and for developing immunotherapies for cancer and other diseases. In particular, we are beginning to define and understand a range of human diseases that are associated with a failure to deliver active perforin to target cells. In this Review, we discuss the current understanding of the structural, cellular and clinical aspects of perforin and granzyme biology.
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            The hnRNP family: insights into their role in health and disease

            Heterogeneous nuclear ribonucleoproteins (hnRNPs) represent a large family of RNA-binding proteins (RBPs) that contribute to multiple aspects of nucleic acid metabolism including alternative splicing, mRNA stabilization, and transcriptional and translational regulation. Many hnRNPs share general features, but differ in domain composition and functional properties. This review will discuss the current knowledge about the different hnRNP family members, focusing on their structural and functional divergence. Additionally, we will highlight their involvement in neurodegenerative diseases and cancer, and the potential to develop RNA-based therapies.
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              Death by a thousand cuts: granzyme pathways of programmed cell death.

              The granzymes are cell death-inducing enzymes, stored in the cytotoxic granules of cytotoxic T lymphocytes and natural killer cells, that are released during granule exocytosis when a specific virus-infected or transformed target cell is marked for elimination. Recent work suggests that this homologous family of serine esterases can activate at least three distinct pathways of cell death. This redundancy likely evolved to provide protection against pathogens and tumors with diverse strategies for evading cell death. This review discusses what is known about granzyme-mediated pathways of cell death as well as recent studies that implicate granzymes in immune regulation and extracellular proteolytic functions in inflammation.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS Pathog
                PLoS Pathog
                plos
                PLoS Pathogens
                Public Library of Science (San Francisco, CA USA )
                1553-7366
                1553-7374
                16 September 2021
                September 2021
                : 17
                : 9
                : e1009818
                Affiliations
                [1 ] Radboud University, Nijmegen, the Netherlands
                [2 ] Department of Pathology, University Medical Center Utrecht, Utrecht, the Netherlands
                [3 ] Center for Translational Immunology, University Medical Center Utrecht, Utrecht, the Netherlands
                Yale University School of Medicine, UNITED STATES
                Author notes

                The authors have declared that no competing interests exist.

                Author information
                https://orcid.org/0000-0002-7188-3184
                https://orcid.org/0000-0002-3962-1408
                https://orcid.org/0000-0002-8526-4456
                Article
                PPATHOGENS-D-21-00507
                10.1371/journal.ppat.1009818
                8445437
                34529743
                43cb6d47-951f-47fb-bc05-50937cf654c5
                © 2021 de Jong et al

                This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                Page count
                Figures: 1, Tables: 1, Pages: 19
                Funding
                The authors received no specific funding for this work.
                Categories
                Review
                Biology and Life Sciences
                Microbiology
                Virology
                Viral Replication
                Biology and Life Sciences
                Microbiology
                Virology
                Viral Transmission and Infection
                Biology and Life Sciences
                Physiology
                Immune Physiology
                Cytokines
                Biology and Life Sciences
                Immunology
                Immune System
                Innate Immune System
                Cytokines
                Medicine and Health Sciences
                Immunology
                Immune System
                Innate Immune System
                Cytokines
                Biology and Life Sciences
                Developmental Biology
                Molecular Development
                Cytokines
                Research and Analysis Methods
                Animal Studies
                Experimental Organism Systems
                Model Organisms
                Mouse Models
                Research and Analysis Methods
                Model Organisms
                Mouse Models
                Research and Analysis Methods
                Animal Studies
                Experimental Organism Systems
                Animal Models
                Mouse Models
                Biology and life sciences
                Biochemistry
                Proteins
                DNA-binding proteins
                Biology and Life Sciences
                Cell Biology
                Cell Processes
                Cell Death
                Apoptosis
                Biology and life sciences
                Genetics
                DNA
                DNA replication
                Biology and life sciences
                Biochemistry
                Nucleic acids
                DNA
                DNA replication
                Biology and life sciences
                Organisms
                Viruses
                DNA viruses
                Herpesviruses
                Human Cytomegalovirus
                Biology and Life Sciences
                Microbiology
                Medical Microbiology
                Microbial Pathogens
                Viral Pathogens
                Herpesviruses
                Human Cytomegalovirus
                Medicine and Health Sciences
                Pathology and Laboratory Medicine
                Pathogens
                Microbial Pathogens
                Viral Pathogens
                Herpesviruses
                Human Cytomegalovirus
                Biology and Life Sciences
                Organisms
                Viruses
                Viral Pathogens
                Herpesviruses
                Human Cytomegalovirus

                Infectious disease & Microbiology
                Infectious disease & Microbiology

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