GNLY

Last updated

GNLY
Protein GNLY PDB 1l9l.png
Available structures
PDB Human UniProt search: PDBe RCSB
Identifiers
Aliases GNLY , 519, D2S69E, LAG-2, LAG2, NKG5, TLA519, granulysin
External IDs OMIM: 188855; HomoloGene: 136805; GeneCards: GNLY; OMA:GNLY - orthologs
Orthologs
SpeciesHumanMouse
Entrez

10578

n/a

Ensembl

ENSG00000115523

n/a

UniProt

P22749

n/a

RefSeq (mRNA)

NM_001302758
NM_006433
NM_012483

n/a

RefSeq (protein)

NP_001289687
NP_006424
NP_036615

n/a

Location (UCSC) Chr 2: 85.69 – 85.7 Mb n/a
PubMed search [2] n/a
Wikidata
View/Edit Human

Granulysin (GNLY) is a protein expressed in most mammals which functions as an antimicrobial peptide released by killer lymphocytes in cytotoxic granules. [3] [4] It is a pore-forming peptide, as it can puncture a microbial cell wall, allowing for other death-inducing enzymes to enter the microbe and cause microptosis. [3] GNLY is inhibited by cholesterol, and is most effective in helping to kill cholesterol-deficient microbes. [5]

Contents

It is part of the saponin-like protein family, and its gene is found on the 2nd chromosome in humans. [3] It is distinguished by its 5 α-helical structure. Its expression is restricted to cytotoxic immune cells such as cytotoxic T cells, NK cells, NKT cells and γδ T cells. [4] [3] Orthologs of this protein are found in most mammal species, such as in cows and pigs, however not in rodents. [5] [3] [4]

Granulysin is also an active player in many diseases, including leprosy and toxic epidermal necrolysis. [3]

Structure

Granulysin has a five alpha-helix structure, and is part of the saposin-like protein family. [5] It is expressed in 2 forms: a 15kDa precursor protein, the translation product, and a 9kDa cytotoxic protein, which is formed after cleavage of the amino and carbonyl ends of the 15kDa protein. [5] [4] [3]

The 15 kDa form consists of 145 amino acids, and is an inactive protein. [3] It exists in its own granule after translation, and release of the protein is triggered by Protein Kinase C (PKC). [5] Its C- and N-Termini function to properly direct the molecule to cytotoxic granules, and are subsequently cleaved once this has been achieved to prevent autolysis. [5] 15 kDa plays other roles in immunological processes, such as in antigen-presenting cell maturation and in immune cell migration. [5]

The 9 kDa form consists of 74 amino acids, and has a cytotoxic function. This molecule is found in cytotoxic granules, along with other cytotoxic molecules, such as granzymes and perforin. [5] [4] [3] The molecule's positive charge allows for binding to phospholipids and cardiolipin, both of which can be found as epitopes on the surfaces of pathogens, and its 2nd and 3rd helices are principle players in lysing foreign or infected cells. [5] [3]

Gene expression

GNLY gene is located on human chromosome 2 and has 5 exons, which code for a 15 kDa protein. [3] The path to transcription has not been elucidated: transcription factors, promoter regions, and pathogen-associated molecular patterns, which likely induce the signaling pathway necessary for the eventual translation of this protein, are unknown. [3] Granulysin is expressed in killer cells, such as cytotoxic T cells and Natural Killer (NK) cells, which hold the cytotoxic granules this protein is contained in. [3] [4] These cells can be found mainly in the epidermis to protect against infection spreading through the skin. [3] In addition, high expression of Granulysin can be found in the placenta to protect fetal epithelial cells. [3]

Function

15 kDa GNLY

The 15 kDa GNLY was originally thought to function exclusively as an inactive precursor of antimicrobial 9 kDa GNLY, however this hypothesis has been recently challenged. [5] 15 kDa has been shown to be located in its own granules and its release is governed by PKC, unlike the 9 kDa GNLY, which is released from its granules via Ca2+. [4] The 15 kDa also functions as an alarmin, molecules capable of starting an inflammatory response. [5] More precisely, 15 kDa GNLY is capable of initiating differentiation of monocytes into dendritic cells. The 15 kDa form is also able to act as a chemoattractant for different cells, such as NK cells, cytotoxic T cells, helper T cells, and in higher concentrations, immature dendritic cells. [5]

9 kDa GNLY

The 9 kDa form functions as a pore-forming protein, as it is able to permeabilize cell membranes. [3] [5] [4] The 9kDa form can cytolyze fungi, yeast, parasites, gram negative, and gram positive bacteria. [6] This protein is also far more effective in targeting bacterial membranes than mammalian membranes, though it can target many different cell types, such as those from fungi and parasites. [4] The 9 kDa form is also inhibited by cholesterol which is present in usually present in mammalian cells, but not in most pathogen cells. [3] [4] This all makes GNLY 1000 times less effective in pore formation in human cells than in microbe cells. However, the precise mechanisms of pore formation is not yet fully understood. [5] [4]

Although GNLY is able to kill pathogens by itself, usually, it cooperates with other proteins from cytotoxic granules, most notably with granzymes. [3] When a cytotoxic cell discovers any infected cell the content of the cytotoxic granules is released by receptor-mediated exocytosis. [3] [4] Perforin, unlike GNLY, binds preferably to cholesterol rich membranes and permeabilizes the infected cell which allows the entry of GNLY and granzymes. [3] GNLY then creates pores in pathogen membranes so granzymes can move into the pathogen where it can cause microptosis. [4] [3] [5]

Granzymes usually cause apoptosis of the infected cell through initiation of the caspase cascade. [4] However, apoptosis can also be initiated by GNLY, due to the presence of cardiolipin in mitochondrial membranes which allows GNLY to create pores in the membrane and causing a release of molecules like cytochrome c, which also leads to apoptosis. [4] [3]

Evolution

GNLY orthologues have been identified in multiple species including pigs, chicken, and cattle. Out of these species (human included) only in cattle 4 functional GNLY where characterized. [7] Generally, such gene duplication can lead to functional specification which seems to be the case of bovine GNLYs because of two reasons. First, the 4 genes are differentially expressed in different tissues. [8] Second, some common cattle pathogens like Histophilus somni and Mannheimia haemolytica have significantly different sensitivity to each of the 4 bovine GNLY. [9]

Clinical significance

Granulysin plays a role in a myriad of diseases, where it can be a positive or negative influence on the immune response. In Leprosy, for example, Granulysin acts to prevent further infection, and infected individuals often have higher expression of killer cells expressing Granulysin. [3] However, in diseases in which Granulysin is expressed in high concentrations individuals can have debilitating or life-threatening symptoms, most notably in autoimmune diseases where cells can be lysed by killer cells. [3]

Toxic epidermal necrolysis

Granulysin plays a large role in Toxic Epidermal Necrolysis (TEN), a disease in which patients suffer from severe blistering, destruction of mucus tissues, fluid loss, and inflamed skin, caused by an immune response to drugs. [10] A drug will often bind to the major histocompatibility complex type I (MHC-I) and cytotoxic T cell receptors, resulting in a cytotoxic immune response. [10] Granulysin has been determined to be the principal player in cell death in this disease. Individuals suffering from TEN were found to have high concentrations of Granulysin in their blister fluid. [10]

Cancer

Granulysin has also been shown to slow the progression of cancers and destroy transformed cells through apoptosis. [5] Patients with high levels of Granulysin in blood serum are better able to fight off metastasis, and generally progression of cancer stages is slow. [5] There is considerable evidence that the 9 kDa form is itself able to destroy tumor cells, however exactly how it does this has not been determined. [5] One mechanism of cell destruction is through initiating calcium increase, which harms the mitochondria and increases the level of cytochrome b, and eventually causing apoptosis. [5]

Related Research Articles

<span class="mw-page-title-main">Cytotoxic T cell</span> T cell that kills infected, damaged or cancerous cells

A cytotoxic T cell (also known as TC, cytotoxic T lymphocyte, CTL, T-killer cell, cytolytic T cell, CD8+ T-cell or killer T cell) is a T lymphocyte (a type of white blood cell) that kills cancer cells, cells that are infected by intracellular pathogens (such as viruses or bacteria), or cells that are damaged in other ways.

<span class="mw-page-title-main">Natural killer cell</span> Type of cytotoxic lymphocyte

Natural killer cells, also known as NK cells, are a type of cytotoxic lymphocyte critical to the innate immune system. They are a kind of large granular lymphocytes (LGL), and belong to the rapidly expanding family of known innate lymphoid cells (ILC) and represent 5–20% of all circulating lymphocytes in humans. The role of NK cells is analogous to that of cytotoxic T cells in the vertebrate adaptive immune response. NK cells provide rapid responses to virus-infected cells, stressed cells, tumor cells, and other intracellular pathogens based on signals from several activating and inhibitory receptors. Most immune cells detect the antigen presented on major histocompatibility complex I (MHC-I) on infected cell surfaces, but NK cells can recognize and kill stressed cells in the absence of antibodies and MHC, allowing for a much faster immune reaction. They were named "natural killers" because of the notion that they do not require activation to kill cells that are missing "self" markers of MHC class I. This role is especially important because harmful cells that are missing MHC I markers cannot be detected and destroyed by other immune cells, such as T lymphocyte cells.

<span class="mw-page-title-main">Perforin-1</span> Mammalian protein found in Homo sapiens

Perforin-1 Perforin (PRF), encoded by the PRF1 gene, is a pore-forming toxic protein housed in the secretory granules of cytotoxic T lymphocytes (CTLs) and natural killer (NK) cells. Together, these cells are known as cytotoxic lymphocytes (CLs).

Granzymes are serine proteases released by cytoplasmic granules within cytotoxic T cells and natural killer (NK) cells. They induce programmed cell death (apoptosis) in the target cell, thus eliminating cells that have become cancerous or are infected with viruses or bacteria. Granzymes also kill bacteria and inhibit viral replication. In NK cells and T cells, granzymes are packaged in cytotoxic granules along with perforin. Granzymes can also be detected in the rough endoplasmic reticulum, golgi complex, and the trans-golgi reticulum. The contents of the cytotoxic granules function to permit entry of the granzymes into the target cell cytosol. The granules are released into an immune synapse formed with a target cell, where perforin mediates the delivery of the granzymes into endosomes in the target cell, and finally into the target cell cytosol. Granzymes are part of the serine esterase family. They are closely related to other immune serine proteases expressed by innate immune cells, such as neutrophil elastase and cathepsin G.

Granzyme B (GrB) is one of the serine protease granzymes most commonly found in the granules of natural killer cells and cytotoxic T cells. It is secreted by these cells along with the pore forming protein perforin to mediate apoptosis in target cells.

<span class="mw-page-title-main">Innate immune system</span> Immunity strategy in living beings

The innate immune system or nonspecific immune system is one of the two main immunity strategies in vertebrates. The innate immune system is an alternate defense strategy and is the dominant immune system response found in plants, fungi, prokaryotes, and invertebrates.

<span class="mw-page-title-main">Antibody-dependent cellular cytotoxicity</span> Cell-mediated killing of other cells mediated by antibodies

Antibody-dependent cellular cytotoxicity (ADCC), also referred to as antibody-dependent cell-mediated cytotoxicity, is a mechanism of cell-mediated immune defense whereby an effector cell of the immune system kills a target cell, whose membrane-surface antigens have been bound by specific antibodies. It is one of the mechanisms through which antibodies, as part of the humoral immune response, can act to limit and contain infection.

<span class="mw-page-title-main">CCL5</span> Mammalian protein found in humans

Chemokine ligand 5 is a protein which in humans is encoded by the CCL5 gene. The gene has been discovered in 1990 by in situ hybridisation and it is localised on 17q11.2-q12 chromosome.

<span class="mw-page-title-main">Immunological synapse</span> Interface between lymphocyte and target cell

In immunology, an immunological synapse is the interface between an antigen-presenting cell or target cell and a lymphocyte such as a T cell, B cell, or natural killer cell. The interface was originally named after the neuronal synapse, with which it shares the main structural pattern. An immunological synapse consists of molecules involved in T cell activation, which compose typical patterns—activation clusters. Immunological synapses are the subject of much ongoing research.

<span class="mw-page-title-main">KLRD1</span> Mammalian protein found in Homo sapiens

CD94, also known as killer cell lectin-like receptor subfamily D, member 1 (KLRD1) is a human gene.

<span class="mw-page-title-main">Degranulation</span> Process by which cells lose secretory granules

Degranulation is a cellular process that releases antimicrobial, cytotoxic, or other molecules from secretory vesicles called granules found inside some cells. It is used by several different cells involved in the immune system, including granulocytes. It is also used by certain lymphocytes such as natural killer (NK) cells and cytotoxic T cells, whose main purpose is to destroy invading microorganisms.

CD16, also known as FcγRIII, is a cluster of differentiation molecule found on the surface of natural killer cells, neutrophils, monocytes, macrophages, and certain T cells. CD16 has been identified as Fc receptors FcγRIIIa (CD16a) and FcγRIIIb (CD16b), which participate in signal transduction. The most well-researched membrane receptor implicated in triggering lysis by NK cells, CD16 is a molecule of the immunoglobulin superfamily (IgSF) involved in antibody-dependent cellular cytotoxicity (ADCC). It can be used to isolate populations of specific immune cells through fluorescent-activated cell sorting (FACS) or magnetic-activated cell sorting, using antibodies directed towards CD16.

<span class="mw-page-title-main">Eosinophil cationic protein</span> Mammalian protein found in Homo sapiens

Eosinophil cationic protein (ECP) also known as ribonuclease 3 is a basic protein located in the eosinophil primary matrix. In humans, the eosinophil cationic protein is encoded by the RNASE3 gene.

<span class="mw-page-title-main">GZMB</span> Protein-coding gene in the species Homo sapiens

Granzyme B is a serine protease that in humans is encoded by the GZMB gene. Granzyme B is expressed by cytotoxic T lymphocytes (CTL) and natural killer (NK) cells.

<span class="mw-page-title-main">CD244</span> Protein found in humans

CD244 also known as 2B4 or SLAMF4 is a protein that in humans is encoded by the CD244 gene.

<span class="mw-page-title-main">Serglycin</span> Protein-coding gene in the species Homo sapiens

Serglycin, also known as hematopoietic proteoglycan core protein or secretory granule proteoglycan core protein, is a protein that in humans is encoded by the SRGN gene. It is primarily expressed in hematopoietic cells and endothelial cells, and is the only known intracellular proteoglycan.

<span class="mw-page-title-main">NCR3</span> Mammalian protein found in Homo sapiens

Natural cytotoxicity triggering receptor 3 is a protein that in humans is encoded by the NCR3 gene. NCR3 has also been designated as CD337 and as NKp30. NCR3 belongs to the family of NCR membrane receptors together with NCR1 (NKp46) and NCR2 (NKp44).

<span class="mw-page-title-main">GZMK</span> Protein-coding gene in the species Homo sapiens

Granzyme K (GrK) is a protein that is encoded by the GZMK gene on chromosome 5 in humans. Granzymes are a family of serine proteases which have various intracellular and extracellular roles. GrK is found in granules of natural killer (NK) cells and cytotoxic T lymphocytes (CTLs), and is traditionally described as being cytotoxic towards targeted foreign, infected, or cancerous cells. NK cells and CTLs can induce apoptosis through the granule secretory pathway, which involves the secretion of granzymes along with perforin at immunological synapses.

<span class="mw-page-title-main">Alan M. Krensky</span>

Alan Krensky is executive for development at Northwestern Medicine and vice dean for development and alumni relations at Northwestern's Feinberg School of Medicine. He was previously senior investigator in the Laboratory of Cellular and Molecular Biology at the National Institutes of Health (NIH) and served as the first director of the Office of Portfolio Analysis and Strategic Initiatives (OPASI) and a deputy director of NIH. He was Associate Dean for Children’s Health and the Shelagh Galligan Professor of Pediatrics at Stanford University.

KHYG-1 is an immortalized cell line that bears the characteristics of NK cells. NK cells are a type of immune cell that are found in blood whose innate function is to kill viral infected cells, cells under stress and cancer cells. The KHYG-1 cell line was established in 1997 in the laboratory of M Yagita in the department of Clinical Immunology and Haematology, Tazuke-Kofukai Medical Research Institute, Kitano Hospital, Osaka, Japan. These cells were derived from the blood of 45-year old female suffering from aggressive Natural killer cell lymphoblastic leukemia/lymphoma. This cell line has been growing continuously, in the presence of IL-2, for 18 months after isolation and its doubling time is around 24-48h. The ability to proliferate was retained even after cryopreservation in liquid nitrogen.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000115523 – Ensembl, May 2017
  2. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 Dotiwala F, Lieberman J (October 2019). "Granulysin: killer lymphocyte safeguard against microbes". Current Opinion in Immunology. 60: 19–29. doi:10.1016/j.coi.2019.04.013. PMC   6800608 . PMID   31112765.
  4. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 Liu X, Lieberman J (April 2020). "Knocking 'em Dead: Pore-Forming Proteins in Immune Defense". Annual Review of Immunology. 38 (1): 455–485. doi:10.1146/annurev-immunol-111319-023800. PMC   7260445 . PMID   32004099.
  5. 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 Sparrow E, Bodman-Smith MD (January 2020). "Granulysin: The attractive side of a natural born killer" (PDF). Immunology Letters. 217: 126–132. doi:10.1016/j.imlet.2019.11.005. PMID   31726187. S2CID   208036617.
  6. ↑ Krensky AM, Clayberger C (March 2009). "Biology and clinical relevance of granulysin". Tissue Antigens. 73 (3): 193–198. doi:10.1111/j.1399-0039.2008.01218.x. PMC   2679253 . PMID   19254247.
  7. ↑ Endsley JJ, Furrer JL, Endsley MA, McIntosh MA, Maue AC, Waters WR, et al. (August 2004). "Characterization of bovine homologues of granulysin and NK-lysin". Journal of Immunology. 173 (4): 2607–2614. doi: 10.4049/jimmunol.173.4.2607 . PMID   15294977. S2CID   22595074.
  8. ↑ Chen J, Huddleston J, Buckley RM, Malig M, Lawhon SD, Skow LC, et al. (December 2015). "Bovine NK-lysin: Copy number variation and functional diversification". Proceedings of the National Academy of Sciences of the United States of America. 112 (52): E7223–E7229. Bibcode:2015PNAS..112E7223C. doi: 10.1073/pnas.1519374113 . PMC   4702975 . PMID   26668394.
  9. ↑ Dassanayake RP, Falkenberg SM, Briggs RE, Tatum FM, Sacco RE (2017-08-21). "Antimicrobial activity of bovine NK-lysin-derived peptides on bovine respiratory pathogen Histophilus somni". PLOS ONE. 12 (8): e0183610. Bibcode:2017PLoSO..1283610D. doi: 10.1371/journal.pone.0183610 . PMC   5565109 . PMID   28827826.
  10. 1 2 3 Harris V, Jackson C, Cooper A (December 2016). "Review of Toxic Epidermal Necrolysis". International Journal of Molecular Sciences. 17 (12): 2135. doi: 10.3390/ijms17122135 . PMC   5187935 . PMID   27999358.

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