SIRPB1- -signal regulatory protein beta 1|Elisa - Clia - Antibody - Protein

Background

Signal regulatory protein beta-1 (SIRPB1) is a transmembrane glycoprotein that is part of the signal regulatory protein (SIRP) family within the immunoglobulin superfamily (IgSF). SIRPB1 is primarily expressed on myeloid cells, such as macrophages, dendritic cells, and granulocytes, and functions as an activating receptor involved in immune regulation, phagocytosis, and cellular signaling. Unlike SIRPA, another family member which interacts with CD47 to deliver inhibitory signals to prevent “self” cell phagocytosis, SIRPB1 typically serves as an activating receptor and does not interact directly with CD47.

SIRPB1 plays a role in modulating immune responses, particularly through its association with DAP12 (DNAX activation protein of 12 kDa), an adaptor molecule containing immunoreceptor tyrosine-based activation motifs (ITAMs). Upon activation, SIRPB1 influences signaling cascades that lead to pro-inflammatory cytokine release, phagocytosis, and cellular migration, especially in response to pathogens or tissue injury. Because of its involvement in immune activation, SIRPB1 has become of interest in cancer, infectious diseases, and inflammatory disorders.

Protein Structure

SIRPB1 has a structure characteristic of the IgSF, with regions specialized for ligand binding, signal transduction, and cellular localization:

Extracellular Domain:

• The extracellular region of SIRPB1 is composed of three immunoglobulin (Ig)-like domains: one variable (V)-type domain at the N-terminus and two constant (C1)-type domains.
• While it resembles the structure of SIRPA in terms of Ig-like domains, SIRPB1 lacks the ability to bind CD47. Instead, its extracellular region may interact with other ligands or molecular patterns on pathogens, though these interactions are less well-defined compared to those of SIRPA.

Transmembrane Domain:

• The transmembrane region of SIRPB1 anchors it to the cell membrane and is crucial for its function as an activating receptor.
• SIRPB1 associates with DAP12, an adaptor protein with ITAM motifs, through the transmembrane domain. This interaction allows SIRPB1 to transmit activating signals by recruiting DAP12 and thus amplifying cellular responses upon activation.

Cytoplasmic Tail:

• SIRPB1 has a short cytoplasmic tail lacking the inhibitory ITIM motifs present in SIRPA. This difference is key to its function as an activating receptor, as SIRPB1 lacks the necessary motifs for recruitment of inhibitory phosphatases such as SHP-1 and SHP-2.
• The absence of ITIM motifs redirects SIRPB1 toward interactions that enhance cellular activation, particularly through DAP12. When DAP12 ITAM motifs are phosphorylated upon SIRPB1 engagement, downstream signaling cascades are triggered to initiate cellular activation responses.

Classification and Subtypes

SIRPB1 is classified within the signal regulatory protein (SIRP) family, which includes several structurally similar proteins, most notably SIRPA and SIRPG. Members of this family can be categorized based on their cytoplasmic regions and functional roles:

SIRPA (SIRP Alpha):

• Functions as an inhibitory receptor by interacting with CD47. It modulates immune responses by inhibiting phagocytosis and cellular activation.

SIRPB1 (SIRP Beta-1):

• Serves as an activating receptor associated with DAP12 and involved in promoting immune responses, including cytokine production, cellular migration, and phagocytosis.

SIRPG (SIRP Gamma):

• Primarily expressed in lymphoid tissues and has limited interactions with CD47. Its functions are not as well characterized, though it may play a role in T cell activation and immune modulation.

Function and Biological Significance

The primary function of SIRPB1 lies in immune activation, particularly in myeloid cells. SIRPB1 modulates immune responses to pathogens and facilitates processes like cellular migration, adhesion, and cytokine production. Key functions of SIRPB1 include:

Immune Activation and Phagocytosis:

• SIRPB1 acts as an activating receptor in immune cells and is central to the immune response against pathogens and in inflammatory conditions. Upon engagement, SIRPB1 triggers the phosphorylation of DAP12-associated ITAMs, which recruit and activate downstream signaling molecules such as Syk and ZAP-70 kinases.
• This cascade enhances phagocytosis and cytokine release, enabling immune cells to respond robustly to microbial invaders, tissue injury, or cellular stress.

Role in Inflammation:

• By promoting the release of pro-inflammatory cytokines, SIRPB1 contributes to the regulation of inflammation. It plays an essential role in acute inflammatory responses by helping immune cells respond effectively to infection or tissue damage.
• SIRPB1’s ability to enhance the release of cytokines like TNF-α, IL-6, and IL-1β from macrophages and dendritic cells ensures a coordinated immune response to injury or infection.

Cell Migration and Adhesion:

• SIRPB1 contributes to cellular adhesion and migration, important processes in immune surveillance, wound healing, and inflammation. When immune cells are activated, SIRPB1 mediates cellular responses that promote movement toward sites of infection or damage.
• This function of SIRPB1 is particularly significant in inflammation and infection as it enhances the ability of immune cells to localize to specific tissues and exert their effects where they are needed most.

Potential Tumor Suppression:

• SIRPB1 has been observed to exert some effects on tumor cells by promoting immune cell recognition and destruction of malignant cells. Some research suggests that SIRPB1 expression may enhance the immune system’s ability to detect and eliminate cancer cells, although this function is still under investigation and is more pronounced in certain cancers.

Clinical Issues

Dysregulation or abnormal expression of SIRPB1 has implications in several diseases and conditions, mainly due to its role in immune activation:

Cancer:

• Abnormal expression or regulation of SIRPB1 has been implicated in certain cancers. In the tumor microenvironment, upregulation of SIRPB1 in immune cells could promote inflammation and antitumor immune responses.
• However, in some cases, tumor cells can modulate SIRPB1 signaling to evade immune surveillance. As a result, SIRPB1 is being explored as a therapeutic target in immuno-oncology to enhance immune responses against tumors.

Autoimmune and Inflammatory Diseases:

• Because SIRPB1 promotes pro-inflammatory responses, dysregulation can lead to chronic inflammation or autoimmune reactions. Overactive SIRPB1 signaling can lead to excessive cytokine release and tissue damage in autoimmune conditions such as rheumatoid arthritis or inflammatory bowel disease.
• Modulating SIRPB1 activity could potentially alleviate symptoms in these conditions by reducing inappropriate or prolonged inflammatory responses.

Infectious Diseases:

• SIRPB1’s role in enhancing immune responses to pathogens makes it relevant in infections. Immune cells expressing SIRPB1 respond robustly to pathogens, releasing cytokines and engaging in phagocytosis. However, excessive or dysregulated activation during infections may lead to severe inflammation, contributing to conditions like sepsis.

Potential Neurological Implications:

• Emerging research suggests a potential role for SIRPB1 in neuroinflammation, as it has been detected on certain cells in the nervous system. Although this function is less understood, dysregulation of SIRPB1 could contribute to neurodegenerative disorders by promoting inflammatory responses in the central nervous system.

Summary

SIRPB1 is an activating receptor predominantly expressed on myeloid cells, where it plays a central role in immune responses, phagocytosis, and inflammation. Structurally, SIRPB1 has three Ig-like domains in its extracellular region, a single transmembrane domain that associates with DAP12, and a short cytoplasmic tail devoid of inhibitory motifs, distinguishing it from other SIRP family members like SIRPA. The absence of ITIM motifs enables SIRPB1 to function as an activator rather than an inhibitor, amplifying immune cell responses upon engagement.

SIRPB1’s functions include promoting immune cell migration, cytokine release, and phagocytosis, particularly in response to infection or tissue damage. Clinically, SIRPB1 has implications in cancer, autoimmune diseases, and infections, as its regulation can impact immune responses in these contexts. Given its significance in immune activation, SIRPB1 is a target of interest in immunotherapy, particularly in enhancing anti-tumor immunity and managing inflammatory diseases. Understanding the structure-function relationship of SIRPB1 provides insights into its role in immunity and potential therapeutic applications.