TNFRSF22

TNFRSF22 Full Name

tumor necrosis factor receptor superfamily, member 22

TNFRSF22 Introduction

TNFRSF22 is a comparatively poorly characterized member of the tumor necrosis factor receptor superfamily, a large family of cell-surface receptors that regulate immunity, inflammation, and cell survival through the recognition of TNF-family ligands. The TNFR superfamily is defined by the presence of characteristic cysteine-rich repeats in the extracellular domain, and TNFRSF22 shares this signature architecture, indicating that it binds a ligand of the TNF family in a manner analogous to its better-studied relatives. Most information about the biology of TNFRSF22 comes from studies of its rodent orthologs, which were identified through their expression in immune tissues and have been implicated in the regulation of T-cell responses and in the control of apoptosis, functions typical of the TNFR family. In humans, the TNFRSF22 locus has been described mainly at the level of genomic and transcript analysis, and its functional characterization has been complicated by the fact that some closely related loci have been inactivated or converted to pseudogenes during primate evolution. The protein, where expressed, is predicted to contain the extracellular ligand-binding domains characteristic of the family together with a cytoplasmic region that may recruit signaling adaptors. Because the TNF receptor superfamily has proven to be a rich source of therapeutic targets, with approved drugs blocking TNF, TRAIL, and other family ligands, continued analysis of less-characterized members such as TNFRSF22 may reveal additional opportunities for modulating immune responses in disease.

Figure 1. TNFRSF22 gene: characterization and roles in immunity and disease of TNFRSF22.

Conserved TNFR Architecture and Family Relationships
TNFRSF22 is classified within the tumor necrosis factor receptor superfamily based on its conserved extracellular cysteine-rich domains, which are the defining feature of the family.
Cysteine-rich domains are small, disulfide-bonded modules that stack to form an elongated ligand-binding domain, and their number and arrangement differ among family members and determine ligand specificity.
The TNFRSF22 gene is located in a region of the genome that contains several related TNF receptor genes, consistent with the expansion of this superfamily through gene duplication.
Phylogenetic analysis indicates that TNFRSF22 is most closely related to receptors involved in immune regulation, and its rodent orthologs are expressed in lymphoid tissues.
Like other TNFR superfamily members, the protein is predicted to be a type I transmembrane receptor with a single membrane-spanning segment and a cytoplasmic domain that can associate with intracellular signaling adaptors.
The extracellular domain of TNFRSF22 may be cleaved to generate a soluble receptor, as occurs for many TNFR family members that thereby act as ligand sinks or as modulators of signaling.
Because the extracellular domains of TNFR family members are structurally similar, the precise ligand and signaling output of TNFRSF22 must be established experimentally rather than inferred from sequence alone.

Immune Regulation, Apoptosis, and Therapeutic Perspectives
Members of the TNF receptor superfamily control a wide range of immune functions, from the activation and proliferation of lymphocytes to the elimination of activated or autoreactive cells through apoptosis.
Studies of the rodent orthologs of TNFRSF22 suggest a role in the regulation of T-cell survival and in the termination of immune responses, functions that, if conserved in humans, would make the receptor relevant to autoimmunity and immune homeostasis.
Because several TNF receptor family members are expressed as both membrane-bound and soluble forms, TNFRSF22 may similarly contribute to the fine-tuning of ligand bioavailability in the immune microenvironment.
The family's track record as a source of therapeutic targets, including antibodies that block or agonize specific receptors, has motivated efforts to deorphanize and functionally characterize its less-studied members.
Understanding whether TNFRSF22 signals cell death, activates inflammatory transcription factors, or serves as a decoy will require the identification of its ligand and the analysis of its signaling complex.
Clarifying the physiological role of TNFRSF22 could therefore extend the therapeutic reach of TNF-superfamily modulation to additional inflammatory and malignant diseases.

Alternate Names for TNFRSF22

TNFRSF22; tumor necrosis factor receptor superfamily, member 22; tumor necrosis factor receptor superfamily member 22; Decoy TRAIL receptor 2; TNF receptor family member SOBa; TNF receptor homolog 2; Tnfrh2; Tnfrsf1al2; Tumor necrosis factor receptor p60 homolog 2; OTTMUSP00000044012

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