SIRPG - signal regulatory protein gamma |Elisa - Clia - Antibody - Protein

Background

Signal Regulatory Protein Gamma (SIRPG) is a member of the signal regulatory protein (SIRP) family, a subset of the immunoglobulin superfamily of cell-surface receptors. SIRPG is encoded by the SIRPG gene located on chromosome 20p13 in humans and is closely related to other family members such as SIRPA (SIRP alpha) and SIRPB (SIRP beta). This receptor plays an important role in immune cell signaling, particularly in immune regulation and cell-cell communication. SIRPG is primarily expressed on cells of the immune system, including T cells and dendritic cells, and plays a significant role in regulating cellular responses involved in immunity. Unlike SIRPA, which interacts with the CD47 ligand on other cells to inhibit macrophage phagocytosis and dendritic cell responses, SIRPG’s role centers on modulating T cell interactions, particularly in the context of immune responses and tissue homeostasis.

Protein Structure

SIRPG is a type I transmembrane glycoprotein with a characteristic structure that includes:

Extracellular Domain:

• The extracellular domain of SIRPG contains two immunoglobulin-like (Ig-like) regions: a variable (V)-type and a constant (C1)-type domain. This configuration is characteristic of the SIRP family and facilitates binding to other Ig-like molecules, particularly in mediating interactions with immune cell surface proteins.
• The V-type domain at the N-terminus is essential for ligand recognition and binding. However, unlike SIRPA, SIRPG does not bind to CD47, suggesting it has a different set of binding partners and functions within immune cell communication.

Transmembrane Domain:

• The transmembrane region of SIRPG consists of a hydrophobic helix that anchors the receptor to the plasma membrane. This region plays an essential role in receptor localization and in mediating intracellular signaling processes, as it positions the intracellular signaling components close to the membrane.

Cytoplasmic Tail:

• The cytoplasmic tail of SIRPG is relatively short compared to other SIRP family members and lacks intrinsic signaling motifs, such as immunoreceptor tyrosine-based inhibitory motifs (ITIMs) found in SIRPA. Instead, SIRPG is associated with activating signaling molecules, indicating its role as an activating receptor in immune cells. For instance, it associates with the CD3 complex on T cells to modulate activation.

Classification and Subtypes

SIRPG is part of the SIRP family, which includes several homologous proteins (e.g., SIRPA and SIRPB) that are structurally related yet functionally distinct. SIRPG can be classified as follows:

• SIRP Family: SIRPG, along with SIRPA and SIRPB, is classified in the SIRP family, a group of transmembrane proteins that act primarily within the immune system.
• Immunoglobulin Superfamily: Due to the presence of Ig-like domains, SIRPG belongs to the broader immunoglobulin superfamily.

There are no known isoforms or subtypes of SIRPG, and the functional diversity in this family comes from its different family members (SIRPA, SIRPB) and their respective roles in immune modulation.

Function and Biological Significance

The primary function of SIRPG is in immune regulation, particularly in modulating T cell function and supporting the establishment of immune synapses. SIRPG is involved in the following biological functions:

T Cell Activation and Interaction:

• SIRPG is highly expressed on T cells and has been shown to play a role in promoting T cell activation through interactions with CD47 and other cell surface ligands. While SIRPG lacks the ability to directly bind CD47, it still supports the immune synapse formation between T cells and antigen-presenting cells (APCs). The engagement of SIRPG on T cells with its binding partners on APCs can amplify T cell responses.

Immune Synapse Formation:

• SIRPG is crucial for the formation of the immune synapse, a specialized junction between T cells and APCs that enables effective communication and antigen recognition. Through signaling pathways initiated by SIRPG, T cells can increase the efficiency of their interactions with APCs, leading to an enhanced immune response.

Cytokine Production and Regulation:

• By modulating T cell activity, SIRPG influences cytokine production, especially of pro-inflammatory cytokines such as IFN-γ. This function is essential for immune responses in viral infections, bacterial defense, and tumor surveillance.

Role in Dendritic Cells:

• SIRPG expression on dendritic cells suggests it may have a role in modulating dendritic cell maturation and function. This could influence the activation of T cells and the presentation of antigens during immune responses, although the specific mechanisms remain under investigation.

Clinical Issues

Alterations in SIRPG expression or function have been linked to various immune-related diseases and cancers, suggesting its role as a modulator of immune homeostasis and potentially as a therapeutic target.

Cancer:

• Dysregulation of SIRPG expression in immune cells has been associated with cancers, where tumor cells often evade immune surveillance. By interfering with immune synapse formation and T cell activation, altered SIRPG function could lead to reduced anti-tumor immunity, allowing tumors to grow and metastasize.
• SIRPG has been considered as a potential target in immunotherapy, aiming to enhance T cell responses against tumors. Enhancing SIRPG function could theoretically improve T cell activation in the tumor microenvironment, promoting immune-mediated tumor destruction.

Autoimmune and Inflammatory Diseases:

• Alterations in SIRPG signaling may also be involved in autoimmune diseases, where T cell activation and immune tolerance are dysregulated. Due to its role in T cell modulation, aberrant SIRPG expression or function could lead to an overactive immune response, contributing to autoimmune conditions.
• Inflammatory disorders, including chronic infections and conditions with excessive immune activation, may be associated with SIRPG dysfunction, given its role in cytokine production and T cell modulation.

Therapeutic Potential:

• SIRPG is a promising therapeutic target in enhancing immune responses, particularly in cancer immunotherapy. Therapeutic modulation of SIRPG to promote T cell activation could offer a new strategy for treating tumors resistant to conventional therapies.
• Its role in immune synapse formation and cytokine regulation makes it a potential target for modulating immune responses in autoimmunity and chronic inflammation, though clinical applications in these areas are still in the experimental stage.

Summary

SIRPG, or signal regulatory protein gamma, is a member of the immunoglobulin superfamily that plays a significant role in the immune system, particularly in modulating T cell activation and immune synapse formation. Structurally, SIRPG features two extracellular Ig-like domains essential for immune cell interactions, a transmembrane domain that anchors it to the cell membrane, and a cytoplasmic tail associated with activating signaling pathways. Though lacking the ITIM motif of SIRPA, SIRPG still engages in immune regulation and facilitates communication between T cells and antigen-presenting cells.

Functionally, SIRPG enhances T cell responses and supports immune synapse formation, which is critical for effective antigen presentation and immune activation. Its role in modulating cytokine production and immune interactions has implications in immune responses, including cancer defense and inflammation. Clinically, altered SIRPG function is associated with cancer immune evasion and possibly with autoimmune diseases and inflammatory conditions. Targeting SIRPG for therapeutic purposes, especially in enhancing T cell responses in cancer, presents a promising avenue for future immunotherapies, particularly where conventional treatments are ineffective.