The N Terminus of Adenovirus Type 12 E1A Inhibits Major Histocompatibility Complex Class I Expression by Preventing Phosphorylation of NF-κB p65 Ser ²⁷⁶ through Direct Binding

Abstract

The immune-escape strategy employed by human oncogenic adenovirus type 12 (Ad12) involves downregulation of major histocompatibility complex class I (MHC-I) transcription by disabling the transactivator NF-B (p50/p65). This is accomplished by the Ad12 E1A protein (E1A-12), which prevents NF-B from becoming phosphorylated by the protein kinase A catalytic subunit (PKAc). In this study, we examined the interactions between E1A-12 and NF-B. Our data show that an E1A-12 mutant retaining the N-terminal 66 amino acids was as effective as the wild-type E1A-12 protein (266 amino acids) in binding p65, preventing phosphorylation of p65-Ser 276 , and inhibiting transactivation. In contrast, the nontumorigenic adenovirus type 5 E1A protein (E1A-5) and other E1A-12 mutants lacking the N-terminal regions were severely defective in these activities. Further studies revealed that an N-terminal peptide consisting of residues 1 to 40 of E1A-12 was able to associate directly with p65 in vitro and prevent PKAc from phosphorylating p65-Ser 276 . In the absence of the N terminus, there is an almost complete loss of E1A-12 binding to p65. These findings provide solid evidence for the role of the E1A-12 N terminus as an NF-B binding domain. Significantly, this study indicates that the E1A-12 N terminus prevents PKAc from gaining access to p65 to account for Ser 276 hypophosphorylation. The E1A-12 N terminus interaction with p65 serves as a key explanation of how Ad12 downregulates MHC-I transcription and contributes to oncogenesis by escaping cytotoxic T lymphocytes.

The N Terminus of Orf Virus-Encoded Protein 002 Inhibits Acetylation of NF-κB p65 by Preventing Ser276 Phosphorylation

“…The human adenovirus type 12(Ad12) E1A protein (E1A-12) inhibits phosphorylation of NF-κB p65 at Ser 276 and causes the loss of DNA binding and transactivation to activate major histocompatibility complex class I expression [10]. Further study found that the last 66 amino acids of the N-terminus of adenovirus type 12 E1A were as effective as the wild-type E1A protein in preventing phosphorylation of NF-κB p65 at Ser 276 and inhibiting major histocompatibility complex class I expression [11]. Our previous report indicated that the ORFV002 gene inhibits the NF-κB signaling pathway by decreasing TNF-α.…”

Inhibition of androgen receptor transactivation function by adenovirus type 12 E1A undermines prostate cancer cell survival

“…For example, E1A12 but not E1A5 can enhance the transcriptional repression function of the orphan NR COUP‐TFII (also known as NR2F2) . E1A12, but not E1A5, has been reported to inhibit the phosphorylation of the p65 subunit of NF‐κB by the protein kinase A catalytic subunit (PKAc), resulting in the suppression of NF‐κB‐mediated transactivation . We report here that E1A12 binds to the AR and suppresses the transactivation function of AR.…”

“…Consequently, E1As of different serotypes may exert considerable functional differences. Indeed, distinct functions have been observed for Ad12 E1A (herein referred to as E1A12) . For example, E1A12 but not E1A5 can enhance the transcriptional repression function of the orphan NR COUP‐TFII (also known as NR2F2) .…”

Widespread evidence of viral miRNAs targeting host pathways

“…Poxviruses and herpes viruses have evolved multiple strategies to disrupt presentation of viral antigens by MHC molecules in order to evade control by T lymphocytes [12]. The adenovirus inhibits MHC-I molecules to evade immune detection [13]. Viruses have also developed mechanisms to bolster the host cell to withstand the viral replication process such as an inhibition of apoptosis [14], an induction of cellular growth or differentiation [15], a recruitment of tissue repair processes such as fibrosis [16], tissue growth [17], and angiogenesis [18].…”