Editorial [Hot Topic: The Type XIV Family of C-type Lectin-like Domain (CTLD) Containing Proteins (Guest Editor: Edward M. Conway)]

The superfamily of proteins that contain C-type lectin-like domains (CTLDs) represents a large number of functionally diverse extracellular proteins (reviewed in [1, 2]). They are subclassified into at least 17 families, primarily according to the architecture of their often multiple domains. The canonical structure of the CTLD features a characteristic double-loop that is stabilized by highly conserved disulfide bridges and hydrophobic and polar interactions. One of these loops, referred to as the long loop region, is particularly flexible and is key for carbohydrate binding and the capacity of the CTLD to bind often simultaneously to one or more ligands. Indeed, this fold is remarkably variable and is estimated to occur with more than 1013 distinct amino acid sequences, analogous to the hypervariable region of immunoglobulins. It is therefore not surprising that the CTLD is highly adaptable, confers multiple functions to the protein, and that it binds not only to sugars, but also to many other structures, including proteins, lipids and inorganic molecules. In this minireview, we focus on the so-called Type XIV CTLD-containing proteins. These are type I transmembrane glycoproteins that have a single N-terminal CTLD that is connected sequentially via a hydrophobic stretch, to a series of 3-6 epidermal growth factor (EGF)-like repeats, a serine-threonine-rich mucin-containing domain, a short transmembrane region, and finally a 20-55 amino acid residue cytoplasmic tail. There are four members of this family, some with several descriptive names that reflect their origins of discovery. These include CD93, thrombomodulin (TM), CD248 (endosialin) and CLEC14a [3]. The latter member is a recent addition to the family, with only limited functional data, and thus will not be discussed in this review. The others represent glycoproteins that have gained wide attention due to discoveries that point to their relevance in human health and disease, particularly in the fields of innate immunity and inflammation. As with many C-type lectins, a common theme of members of the Type XIV family is their participation in modulating the response to injury, each in its own way. As will be seen in this minireview, TM, CD93 and CD248 differentially regulate innate immunity, cell proliferation and inflammation by virtue of their being comprised of additional structural motifs, having unique cellular and temporal patterns of expression, and interacting with distinct protein partners. TM is prominently expressed by endothelial cells, some myeloid cells, and dendritic cells. The CTLD of TM is the only one of the Type XIV family members in which a function has been ascribed and ligands have been identified. The CTLD clearly dampens inflammation and innate immune responses in a variety of disease models [4]. It does so in concert with three of its six EGF-like repeats, which serve primarily to protect against excess clot formation. As Morser describes in this issue of CDT [5], TM plays a central protective role in innate immunity and hemostatic control, and soluble fragments of TM are holding promise for therapies in a range of difficult-to-treat diseases. Interestingly, CD93 may have arisen from a gene duplication of the gene for TM. CD93 is similarly expressed by endothelial and myeloid cells, but also by platelets, hematopoietic stem cells, and several lymphocyte subtypes [6]. In contrast to TM, the EGF-like repeats of CD93 are not known to regulate coagulation. However, as Bohlson and colleagues report [7] CD93 also plays a key role in innate immunity by promoting phagocytosis and leukocyte adhesion. More recently revealed, CD93 participates in acquired immunity by maintaining the integrity of antibody-producing plasma cells. These properties are probably relevant in human disease, as CD93 is increasingly being shown to modulate multiple inflammatory and immune diseases and at least in some conditions, polymorphisms may portend an increased risk of inflammatory vascular disease. For a few reasons, CD248 stands somewhat apart from the rest of the family. In spite of early reports to the contrary, CD248 is not expressed by endothelial cells [8]. Rather, it is found in activated stromal and perivascular cells in tumors and inflammatory lesions and is almost undetectable in most adult tissues. It also uniquely contains a complement regulatory motif residing between the CTLD and EGF-like containing domain, the function of which remains unknown. Like TM, its gene is intronless [9]. Like CD93, it contains a C-terminal PDZ-binding motif with unknown function, but which is important for endocytosis of CD248 [10]. Generally opposing TM and CD93, CD248 appears to promote inflammation [11], possibly via intracellular signaling via its cytoplasmic tail and/or through extracellular matrix ligands that interact with the ectodomain. This minireview provides a comprehensive update on three important CTLD-containing proteins, members of a structurally related family, all of which play important yet distinct roles in innate immunity. It is intriguing that in spite of the structural similarities of their CTLDs and their overall domain architectures, TM, CD93 and CD248 do indeed display profound functional differences. Is this based on the variability within the CTLDs themselves? Or are there multiple context-dependent factors that are responsible? What common regulatory factors orchestrate the differential expression and function of the CTLDcontaining proteins to optimize the organism's response to injury and to most efficiently promote tissue repair? Are there more direct interactions between these molecules that in some situations may be expressed at the same site? Are there bioactive soluble forms of CD248, similar to those for TM and CD93 that are being exploited for diagnostic and therapeutic use? Hopefully this review will encourage further study to address some of these questions that lead to new diagnostic approaches and innovative therapeutic strategies.