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Expression, Function, and Molecular Properties of the Killer Receptor Ncr1-Noé
Ariella Glasner1, Hrvoje Simic2, Karmela Miklić2
1Lautenberg Center for General and Tumor Immunology, Hebrew University Hadassah Medical School, Jerusalem 91120, Israel;
Abstract:
NK cells kill various cells using activating receptors, such as the natural cytotoxicity receptors (NCRs). NKp46 is a major NCR and is the only NCR expressed in mice (denoted Ncr1). Using Ncr1-deficient mice (Ncr1(gfp/pfp)) we demonstrated that Ncr1 controls various pathologies, and that in its absence Ncr1-related functions are impaired. In 2012, another Ncr1-related mouse was generated, named Noé, in which a random mutation, W32R, in position 32, impaired the Ncr1-Noé cell surface expression. Interestingly, in the Noé mice, Ncr1-dependent deficiencies were not observed. Additionally, the Noé-NK cells were hyperactivated, probably due to increased Helios expression, and the Noé mice demonstrate increased clearance of influenza and murine CMV. In contrast, in the Ncr1(gfp/pfp) mice infection with influenza was lethal and we show in the present study no difference in murine CMV infection between Ncr1(gfp/pfp) and wild-type (WT) mice. Because the foremost difference between the Noé and Ncr1(gfp/gfp) mice is the presence of a mutated Ncr1-Noé protein, we studied its properties. We show that Ncr1-Noé and various other Ncr1 mutants in position 32 can be expressed on the surface, albeit slowly and unstably, and that ligand recognition and function of the various Ncr1-Noé is similar to the WT Ncr1. We further show that the glycosylation pattern of Ncr1-Noé is aberrant, that the Ncr1-Noé proteins accumulate in the endoplasmic reticulum, and that the expression of Ncr1-Noé proteins, but not WT Ncr1, leads to increased Helios expression. Thus, we suggest that the NK hyperactivated phenotype observed in the Noé mice might result from the presence of the Ncr1-Noé protein.
Insights
Natural killer (NK) cells use activating receptors like NKp46 (Ncr1) to kill cells. A mutated Ncr1-Noé protein in mice leads to NK cell hyperactivation and improved viral clearance, unlike Ncr1 deficiency.
Area of Science:
- Immunology
- Cell Biology
- Virology
Background:
- Natural killer (NK) cells are crucial for innate immunity, eliminating infected or cancerous cells via activating receptors.
- NKp46 (Ncr1) is a major activating receptor and the only natural cytotoxicity receptor (NCR) expressed in mice.
- Ncr1-deficient mice exhibit impaired NK cell functions and increased susceptibility to certain infections.
Purpose of the Study:
- To investigate the functional consequences of a specific mutation (W32R) in the Ncr1 gene, leading to the Ncr1-Noé variant.
- To elucidate the mechanism behind the hyperactivated NK cell phenotype observed in Noé mice.
- To compare the pathological outcomes in Ncr1-deficient mice versus Noé mice during viral infections.
Main Methods:
- Generation and characterization of Ncr1-deficient (Ncr1(gfp/pfp)) and Ncr1-Noé mutant mice.
- Analysis of NK cell surface expression, glycosylation patterns, and intracellular trafficking of Ncr1 variants.
- Assessment of NK cell activation, ligand recognition, and functional responses in vitro and in vivo.
- Evaluation of viral clearance and survival rates in response to influenza and murine cytomegalovirus (MCMV) infections.
Main Results:
- Ncr1-Noé and other position 32 mutants exhibit slow, unstable surface expression but retain ligand recognition and basic function.
- Aberrant glycosylation and endoplasmic reticulum accumulation of Ncr1-Noé proteins were observed.
- Ncr1-Noé expression, unlike wild-type Ncr1, significantly increases Helios expression in NK cells.
- Noé mice show enhanced clearance of influenza and MCMV, contrasting with lethal influenza in Ncr1(gfp/pfp) mice.
Conclusions:
- The Ncr1-Noé mutation alters protein processing and trafficking, leading to aberrant glycosylation and ER retention.
- Increased Helios expression in NK cells of Noé mice is linked to the presence of the Ncr1-Noé protein.
- The Ncr1-Noé protein likely induces NK cell hyperactivation, contributing to improved viral control in Noé mice.
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