ATF4 Signaling in HIV-1 Infection: Viral Subversion of a Stress Response Transcription Factor

Abstract

Cellular integrated stress response (ISR), the mitochondrial unfolded protein response (UPRmt), and IFN signaling are associated with viral infections. Activating transcription factor 4 (ATF4) plays a pivotal role in these pathways and controls the expression of many genes involved in redox processes, amino acid metabolism, protein misfolding, autophagy, and apoptosis. The precise role of ATF4 during viral infection is unclear and depends on cell hosts, viral agents, and models. Furthermore, ATF4 signaling can be hijacked by pathogens to favor viral infection and replication. In this review, we summarize the ATF4-mediated signaling pathways in response to viral infections, focusing on human immunodeficiency virus 1 (HIV-1). We examine the consequences of ATF4 activation for HIV-1 replication and reactivation. The role of ATF4 in autophagy and apoptosis is explored as in the context of HIV-1 infection programmed cell deaths contribute to the depletion of CD4 T cells. Furthermore, ATF4 can also participate in the establishment of innate and adaptive immunity that is essential for the host to control viral infections. We finally discuss the putative role of the ATF4 paralogue, named ATF5, in HIV-1 infection. This review underlines the role of ATF4 at the crossroads of multiple processes reflecting host-pathogen interactions.

Keywords: AIDS; ER stress; ISR; UPR; immunity; mitochondria.

Figure 1

A model of regulation of ATF4 and integrated stress kinases during HIV-1 infection. Blue arrows correspond to interactions demonstrated by the literature in the context of HIV-1 infection. Yellow arrows correspond to reports in a different context. Besides ATF4, cellular proteins are indicated in green and HIV-1 proteins in red. ISR kinases can be activated by ER stress (PERK and PKR), HIV-1 RNA (PKR), heme depletion and cleavage of DELE1 by OMA1 after mitochondrial stress (HRI), amino acid deprival (GCN2), oxidative stress (FAM69C), and proteotoxic stress (MARK2). Several cellular and viral proteins modulate ISR kinases during HIV-1 infection, as TRBP and ADAR1 and the HIV-1 Tat protein preventing the phosphorylation of eIF2α and increasing ATF4 synthesis. The viral Vpu protein stabilizes ATF4 by opposing its ubiquitination by the SCF-βTrCP complex. Created with BioRender.com (accessed on 18 January 2024).

Figure 2

ATF4 in the HIV-1 cycle. The HIV-1 cycle begins with the attachment of the virus to the cell surface thanks to the CD4 and CCR5 receptors (1). This allows the fusion between the viral envelope and the host cell membrane (2). During this phase, the viral nucleocapsid enters the cell cytoplasm. Single-stranded RNA molecules are then retro-transcribed in the nucleus (3). The viral DNA then integrates into the host cell genome (4), where it can remain latent until reactivation. The exit from the latency is stimulated by ATF4, which, in cooperation with the viral protein Tat, activates the HIV-1 promoter located in the LTR region of the viral DNA leading to viral RNA (5). These HIV-1 messenger RNAs are exported from the nucleus to be translated (6) into proteins that assemble to form the internal structure of viral particles (7). Budding from the cell membrane (8) culminates with the release and maturation of viral particles in the extracellular environment (9). ATF4 is also capable of inducing the activation of target genes involved in cellular processes such as autophagy, inflammation, and apoptosis. Adapted from “Disease Mechanism–Infectious Diseases, HIV Replication Cycle”, by BioRender.com. Retrieved from https://app.biorender.com/biorender-templates (accessed on 18 January 2024).

Figure 3

ATF4 signaling pathways during HIV-1 infection. Blue arrows correspond to interactions demonstrated in HIV-1 literature. Yellow arrows correspond to other contexts. Besides ATF4, cellular proteins appear in green and HIV-1 proteins in red. The genes in red are some of the pro-apoptotic genes induced by ATF4/ATF3 or ATF4/CHOP dimers and ATF4 dimerizing with a partner that remains to be determined. ATF5 also regulates the immune response at least by controlling immune cell differentiation. ATF4 also controls the expression of several pro-apoptotic genes including TID1/DNAJA3, G0S2, and TP53BP2. The genes in green are involved in ATF4-mediated survival as TMBIM5. Genes in purple are implicated in ATF4-induced autophagy like WIPI1, ATG12, ATG10, ATG16L1, ATG7, MAP1lc3B, GABARAPl2, p62/SQSTM1, NBR1, and REDD1. Finally, genes in pink are genes related to inflammation that are induced by ATF4 in a dimer with phosphorylated c-Jun or an undefined partner. Other genes activated by the phosphorylated ATF4/c-Jun dimer include RANTES and sICAM-1. Not shown in this diagram is IRF7 activation, which induces the production of type I and II interferons, and then activates the PKR/eIF2α/ATF4 pathway. Created with BioRender.com (accessed on the 18 January 2024).

Figure 4

Comparison of ATF4 and ATF5 proteins. Percentages of identity and similarity between amino acid sequences of ATF4 and ATF5 are shown. Both proteins contain a bZIP domain comprising a basic region for DNA binding and a leucine zipper motif for dimerization. ATF4 interacts with the p300 protein thanks to its N-terminal region (1–85), allowing its acetylation by p300 on lysine 311. Hydroxylation on prolines 60 and 235 results in a decrease in ATF4 transcriptional activity. ATF4 has a DSGICMS motif recognized by the β-TrCP factor to induce its degradation by the proteasome, following its phosphorylation by β-TrCP on its serine 219. Phosphorylation of ATF4 by β-TrCP on serine 224 also participates in this regulation. ATF5 can be acetylated on its lysine 29 by p300. The first 21 amino acids of ATF5 are involved in stabilizing the protein in response to Interleukin-1β. The post-translational modifications of ATF4 and ATF5 are shown in the following color code: acetylation in orange, hydroxylation in blue, phosphorylation in green, ubiquitination in yellow, and SUMOylation in purple. Created with BioRender.com (accessed on 18 January 2024).