Regulation of NKG2D Expression and Signaling by Endocytosis
Rosa Molfetta1, Linda Quatrini1, Beatrice Zitti1
1Department of Molecular Medicine, Institute Pasteur-Fondazione Cenci Bolognetti, 'Sapienza' University of Rome, 00161, Rome, Italy.
Abstract:
NKG2D is an activating receptor that can bind to a large number of stress-induced ligands that are expressed in the context of cancer or viral infection. This receptor is expressed on many cytotoxic lymphocytes, and plays a crucial role in antitumor and antiviral immune responses. However, exposure to NKG2D ligand-expressing target cells promotes receptor endocytosis, ultimately leading to lysosomal receptor degradation and impairment of NKG2D-mediated functions. Interestingly, before being degraded, internalized receptors can signal from the endosomal compartment, leading to the appropriate activation of cellular functional programs. This review summarizes recent findings on ligand-induced receptor internalization, with particular emphasis on the role of endocytosis in the control of both NKG2D-mediated intracellular signaling and receptor degradation.
Insights
Natural killer group 2D (NKG2D) receptor internalization impairs anti-cancer immunity. However, signaling from endosomes before degradation can still activate immune responses, offering new therapeutic targets.
Area of Science:
- Immunology
- Cell Biology
- Molecular Biology
Background:
- NKG2D is a key activating receptor on cytotoxic lymphocytes crucial for anti-tumor and anti-viral immunity.
- Ligand binding triggers NKG2D receptor endocytosis, leading to degradation and reduced immune function.
Purpose of the Study:
- To review recent findings on NKG2D receptor internalization.
- To emphasize the role of endocytosis in NKG2D signaling and degradation.
Main Methods:
- Literature review of studies on NKG2D receptor trafficking and signaling.
- Analysis of endocytosis pathways and their impact on immune cell function.
Main Results:
- Ligand-induced endocytosis of NKG2D receptors leads to their degradation in lysosomes.
- Internalized NKG2D receptors can signal from endosomes before degradation.
- Endosomal signaling can activate cellular functional programs relevant to immune responses.
Conclusions:
- NKG2D receptor internalization is a complex process impacting immune responses.
- Endocytosis controls both NKG2D-mediated signaling and receptor fate.
- Targeting endosomal signaling offers potential therapeutic strategies for enhancing anti-tumor and anti-viral immunity.
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