pH-dependent recognition of apoptotic and necrotic cells by the human dendritic cell receptor DEC205

Cao, Longxing; Shi, Xiangyi; Chang, Haishuang; Zhang, Qinfen; He, Yongning

doi:10.1073/pnas.1505924112

Cited by 45 publications

(50 citation statements)

References 50 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In our previous studies, we identified a single mutant (H129E) on the smaller ring that abolished the DEC205 binding to apoptotic and necrotic cells (Fig. 3A) (27). Similarly, ELISA results showed that this mutant had no binding affinity to keratins either (Fig.…”

Section: Dec205 Binds Keratins At Acidic Ph Through Its N-terminal Smmentioning

confidence: 59%

“…Their ectodomains begin with a cysteine-rich domain (CysR), followed by a fibronectin type II domain (FNII) and 8 (10 for DEC205) C-type lectin-like domains (CTLDs). Recently, our data indicate that the ectodomain of DEC205 adopts a double-ringed conformation at acidic pH and also show that DEC205 recognizes apoptotic and necrotic cells specifically in acidic environments through its N-terminal smaller ring (27), suggesting that it mediates a different dead cell recognition pathway from the previously identified receptors. However, because the physiological ligand(s) of DEC205 has not been found, the mechanism of this pathway remains unknown.…”

mentioning

confidence: 57%

“…S2B), thus confirming the in vitro binding results of DEC205 and keratins. Our previous results indicated that DEC205 could bind to the apoptotic and necrotic cells specifically at acidic pH (27). Therefore, if keratins are the cellular ligands of DEC205, the keratin tail fragments identified above should be able to inhibit the binding of DEC205 to dead cells.…”

Section: Dec205 Binds Keratins At Acidic Ph Through Its N-terminal Smmentioning

confidence: 90%

“…3 C and D), which adopts a ring-shaped conformation (the smaller ring) at acidic pH (Fig. 3A) (27). In contrast, the DEC205 fragment FNII∼CTLD6, which forms a larger ring at acidic pH (Fig.…”

Section: Dec205 Binds Keratins At Acidic Ph Through Its N-terminal Smmentioning

confidence: 95%

“…DEC205 belongs to the mannose receptor family (24), which includes five members: the mannose receptor, DEC205, Endo180, PLA2R, and FcRY (25). Structural results indicate that these receptors share similar structural features (26)(27)(28). Their ectodomains begin with a cysteine-rich domain (CysR), followed by a fibronectin type II domain (FNII) and 8 (10 for DEC205) C-type lectin-like domains (CTLDs).…”

mentioning

confidence: 99%

See 4 more Smart Citations

Keratin mediates the recognition of apoptotic and necrotic cells through dendritic cell receptor DEC205/CD205

Cao

Chang

Shi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

Clearance of dead cells is critical for maintaining homeostasis and prevents autoimmunity and inflammation. When cells undergo apoptosis and necrosis, specific markers are exposed and recognized by the receptors on phagocytes. DEC205 (CD205) is an endocytotic receptor on dendritic cells with antigen presentation function and has been widely used in immune therapies for vaccine generation. It has been shown that human DEC205 recognizes apoptotic and necrotic cells in a pH-dependent fashion. However, the natural ligand(s) of DEC205 remains unknown. Here we find that keratins are the cellular ligands of human DEC205. DEC205 binds to keratins specifically at acidic, but not basic, pH through its N-terminal domains. Keratins form intermediate filaments and are important for maintaining the strength of cells and tissues. Our results suggest that keratins also function as cell markers of apoptotic and necrotic cells and mediate a pH-dependent pathway for the immune recognition of dead cells. T he immune system is responsible for removing self-antigens such as dead cells to maintain tissue homeostasis and prevent autoimmunity (1-3). Dead cells are recognized and engulfed by phagocytes through their cell surface receptors (4), leading to either immune activation or tolerance (5-8). A number of receptors have been found to be able to mediate the clearance of dead cells (3); for example, CD14 (9), CD36 (10), integrin (11), PtdSerR (12), CLEC9A (13-15), and TIM receptor family members (16). Among known dead cell markers, phosphatidylserine (PS) is the most common one that can be recognized by several receptors such as CD36, PtdSerR, and TIM receptors, and acts as an "eatme" signal for phagocytes mediating dead cell clearance (4). Other than PS, several cellular proteins have also been found to be able to perform the similar function. For example, actin filaments can be recognized by CLEC9A as a damaged cell marker (13, 15). The recognition of different dead cell markers by phagocytes provides an efficient way to remove cell debris completely.Keratins are important cytoskeletal components and form intermediate filaments in cytoplasm. There are 54 known members in the keratin family that are divided into two types based on their isoelectric points and sequences (17). Keratin monomers can assemble into bundles first and then form fibrous filaments ∼10 nm in diameter, which act as a scaffold and provide mechanical support for maintaining the strength and toughness of cells and tissues (18,19). Recently, evidence has accumulated showing that keratins play physiological roles in addition to their structural functions, for example, in cell growth, proliferation, mobility, apoptosis, and tumorigenesis (18,20,21). DEC205 (CD205 or Ly75, molecular mass of 205 kDa) is an endocytotic receptor highly expressed on dendritic cells and thymic epithelial cells (8,22) and capable of inducing either tolerance or immunity in the absence or presence of inflammatory stimuli (23). DEC205 belongs to the mannose receptor family (24), which includes...

show abstract

Section: Dec205 Binds Keratins At Acidic Ph Through Its N-terminal Smmentioning

confidence: 59%

mentioning

confidence: 57%

Section: Dec205 Binds Keratins At Acidic Ph Through Its N-terminal Smmentioning

confidence: 90%

Section: Dec205 Binds Keratins At Acidic Ph Through Its N-terminal Smmentioning

confidence: 95%

mentioning

confidence: 99%

See 3 more Smart Citations

Keratin mediates the recognition of apoptotic and necrotic cells through dendritic cell receptor DEC205/CD205

Cao

Chang

Shi

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

View full text Add to dashboard Cite

show abstract

Secondary Sites of the C‐type Lectin‐Like Fold

Lefèbre,

Falk,

Ning

et al. 2024

Chemistry A European J

View full text Add to dashboard Cite

C‐type lectins are a large superfamily of proteins involved in a multitude of biological processes. In particular, their involvement in immunity and homeostasis has rendered them attractive targets for diverse therapeutic interventions. They share a characteristic C‐type lectin‐like domain whose adaptability enables them to bind a broad spectrum of ligands beyond the originally defined canonical Ca2+‐dependent carbohydrate binding. Together with variable domain architecture and high‐level conformational plasticity, this enables C‐type lectins to meet diverse functional demands. Secondary sites provide another layer of regulation and are often intricately linked to functional diversity. Located remote from the canonical primary binding site, secondary sites can accommodate ligands with other physicochemical properties and alter protein dynamics, thus enhancing selectivity and enabling fine‐tuning of the biological response. In this review, we outline the structural determinants allowing C‐type lectins to perform a large variety of tasks and to accommodate the ligands associated with it. Using the six well‐characterized Ca2+‐dependent and Ca2+‐independent C‐type lectin receptors DC‐SIGN, langerin, MGL, dectin‐1, CLEC‐2 and NKG2D as examples, we focus on the characteristics of non‐canonical interactions and secondary sites and their potential use in drug discovery endeavors.

show abstract