Adenovirus RID complex enhances degradation of internalized tumour necrosis factor receptor 1 without affecting its rate of endocytosis

Abstract

The receptor internalization and degradation (RID) complex of adenovirus plays an important role in modulating the immune response by downregulating the surface levels of tumour necrosis factor receptor 1 (TNFR1), thereby inhibiting NF-kB activation. Total cellular content of TNFR1 is also reduced in the presence of RID, which can be inhibited by treatment with lysosomotropic agents. In this report, surface biotinylation experiments revealed that, although RID and TNFR1 were able to form a complex on the cell surface, the rate of TNFR1 endocytosis was not affected by RID. However, the degradation of internalized TNFR1 was enhanced significantly in the presence of RID. Therefore, these data suggest that RID downregulates TNFR1 levels by altering the fate of internalized TNFR1 that becomes associated with RID at the plasma membrane, probably by promoting its sorting into endosomal/lysosomal degradation compartments.The successful replication and survival of viruses in the host requires evasion of the immune system. Many of the immunomodulatory genes of adenovirus (Ad) are encoded in early region 3 (E3) (Fessler et al., 2004b;Horwitz, 2004). The E3 receptor internalization and degradation (RID) complex, composed of two RIDa and one RIDb subunits, downregulates a specific set of plasma-membrane receptors, including FAS (Shisler et al., 1997;Elsing & Burgert, 1998;Tollefson et al., 1998), tumour necrosis factor (TNF)-related apoptosis-inducing ligand receptor 1 (TRAIL-R1) (Benedict et al., 2001;Tollefson et al., 2001) and epidermal growth factor receptor (EGFR) (Carlin et al., 1989;Tollefson et al., 1991). Together with another E3 protein, E3/6.7K, RID also reduces the surface expression of TRAIL-R2 (Lichtenstein et al., 2004). Whilst both of the RID subunits are critical for the downregulation of FAS and TRAIL receptors, it appears that the RIDa subunit is sufficient to downregulate EGFR under certain experimental conditions (Hoffman et al., 1990). Recently, we demonstrated that RID also downregulates TNFR1, thereby inhibiting TNF-induced NF-kB activation, which mediates the transcription of a large number of genes involved in inflammation and immune responses such as chemokine expression (Fessler et al., 2004a;Delgado-Lopez & Horwitz, 2006).In vivo experiments have shown that RID is an essential component of the Ad E3 cassette, which facilitates transplantation of allogeneic pancreatic cells (Efrat et al., 1995) and decreases autoimmune type 1 diabetes incidence (von Herrath et al., 1997;Efrat et al., 2001;Pierce et al., 2003). To potentially use RID as a therapeutic immunomodulator, it is important to elucidate the molecular mechanism of RIDmediated downregulation of receptors. We recently showed that the tyrosine sorting motifs of RIDb and clathrin play important roles in the downregulation of TNFR1, and that RID-mediated TNFR1 degradation occurs via an endosomal/ lysosomal pathway (Chin & Horwitz, 2005). In this report, we further examined the effect of RID on TNFR1 trafficking. Specifically, we tested the abili...

Intestinal Anti-Inflammatory Activity of Lentinan: Influence on IL-8 and TNFR1 Expression in Intestinal Epithelial Cells

“…demonstrated that the receptor internalization and degradation (RID) complex, composed of two RIDα and one RIDβ protein subunits, of adenovirus plays an important role in modulating the immune response by down-regulating the surface levels of TNFR1, thereby inhibiting NF-κB activation [52]. They showed that RID is able to associate with TNFR1 on the cell surface, both RID and clathrin play an important role in mediating delivery of TNFR1 to intracellular sites that accelerate its degradation [53].…”

The Cytomegaloviral Protein pUL138 Acts as Potentiator of Tumor Necrosis Factor (TNF) Receptor 1 Surface Density To Enhance ULb′-Encoded Modulation of TNF-α Signaling

“…RID downregulates TNFR1 surface levels and is necessary and sufficient to block TNF-induced NF-B and AP-1 activation (16). RID interacts with TNFR1 and acts by clathrin-dependent TNFR1 internalization and subsequent endolysosomal degradation (11) without affecting the rate of endocytosis itself (12). In contrast, the transmembrane protein pUL138 is directed to the trans-Golgi compartment (48), where it forms complexes with TNFR1 before TNFR1 molecules are released in a signaling-competent state to the plasma membrane, allowing potentiated ligand-triggered downstream signaling.…”

RID: Evaluation of the Possible Inhibiting Effect of the Proinflammatory Signaling Induced by TNF-α through NF-κβ and AP-1 in Two Cell Lines of Breast Cancer

“…Adenoviruses express several immunoregulatory genes grouped in the early expression cassette 3 (E3) [10] with various functions during infection. The E3-14.7K protein inhibits apoptosis induced by TNF-α [11], and the E3-10.4K/E3-14.5K proteins, also known as receptor internalization and degradation (RID), block apoptosis and inhibit secretion of arachidonic acid induced by TNF-α [12], reducing the cell surface expression of Fas, EGFR, TRAIL-R1, TRAIL-R2 [13], and TNFR [14] as well as inhibit lipopolysaccharide signaling (LPS), NF-kβ activation, JNK activation, and IL-8 and MCP-1 secretion, without altering the expression on the cell surface of the TLR-4 receptor in astrocytoma cell line [15].…”