The role of 14-3-3 proteins in cell signalling pathways and virus infection

Abstract

14-3-3 proteins are highly conserved in species ranging from yeast to mammals and regulate numerous signalling pathways via direct interactions with proteins carrying phosphorylated 14-3-3-binding motifs. Recent studies have shown that 14-3-3 proteins can also play a role in viral infections. This review summarizes the biological functions of 14-3-3 proteins in protein trafficking, cell-cycle control, apoptosis, autophagy and other cell signal transduction pathways, as well as the associated mechanisms. Recent findings regarding the role of 14-3-3 proteins in viral infection and innate immunity are also reviewed.

Keywords: 14-3-3 proteins; biological function; innate immunity; viral infection.

FIGURE 1

The main roles of 14‐3‐3 Proteins in cell signalling pathway. A, Regulation of 14‐3‐3 proteins in cell cycle. In G2/M phase, 14‐3‐3 proteins interact with CDC25C, which prevents CDC25C‐mediated interaction between CDK1 and Cyclin, thus blocking the cell cycle in M phase. CDC25C mediated by CHK1 is phosphorylated at Ser216 and binds to 14‐3‐3 proteins, making CDC25C blocked in the cytoplasm and inhibiting the cell cycle. In the G1/S phase, CHK1 kinase phosphorylates CDC25A at Ser178 and Thr507. Then, CDC25A binds to 14‐3‐3 proteins, thereby blocking the activation of the CDK/Cyclin complex, resulting in G1/S phase blockade. 14‐3‐3 proteins can degrade P21 in an ubiquitin‐dependent manner, thereby promoting the G1/S phase of the cell cycle. B, Regulation of 14‐3‐3 proteins in apoptosis. The AKT phosphorylates Ser136 on Bad, and then Bad interacts with 14‐3‐3 proteins, blocking BAD into the cytoplasm and not entering the mitochondria, thereby inhibiting apoptosis. The interaction of ASK1 with 14‐3‐3 proteins after the phosphorylation at Ser996, they form a complex, thereby inhibiting the activity of ASK1 kinase, thereby inhibiting apoptosis. As an anti‐apoptotic factor, 14‐3‐3 proteins interact with FKHRL1, which is phosphorylated at Thr24, to inhibit FKHRL1‐induced apoptosis. C, Regulation of 14‐3‐3 proteins in autophagy. 14‐3‐3 proteins can interact with phosphorylated PRAS40 which is at Ser183 and Ser221 and phosphorylated TSC2 at Ser939, thereby inhibiting the initiation of autophagy. 14‐3‐3 proteins interact with phosphorylated ULK1 at Ser555, blocking the formation of pre‐autophagosomes induced by ULK1, thereby inhibiting cellular autophagy. 14‐3‐3 proteins interact with hVps34 at a phosphorylated site Ser212, and the interaction between them hinders the activity of hVps34. Beclin‐1 is also an important molecule in the formation of autophagosomes. Beclin‐1 interacts with 14‐3‐3 proteins through phosphorylation at Ser234 and Ser295, thereby promoting tumourigenesis by inhibiting autophagy

FIGURE 2

14‐3‐3 proteins regulate innate immunity. RIG‐I and MDA5 recognize both short dsRNA and long dsRNA viruses, respectively, and are then transferred to the mitochondria to interact with MAVS, induce IRF3, IRF7 and NF‐κB activation, promoting the production of IFN and various inflammatory factors. 14‐3‐3ε plays a crucial role in the transfer of RIG‐I to mitochondrial MAVS and is a partner of RIG‐I interaction and promotes the translocation complex containing RIG‐I, 14‐3‐3ε and TRIM25 formation (the dotted circle indicated in the figure). 14‐3‐3ε interacts with RIG‐I and TRIM25, and stabilizes the interaction between the RIG‐I and TRIM25 proteins. 14‐3‐3η promotes the transport of MAD5 from the cytoplasm to the mitochondrial membrane through interaction with MDA5, thereby enhancing and boosting the MAD5‐mediated antiviral response. However, the interaction between the ZIKV NS3 protein and 14‐3‐3ε hinders the transduction of RIG‐I, while interaction with 14‐3‐3η hinders the transduction of MDA5, further inhibiting innate immunity and promoting its own virus replication. In addition, the interaction of the EBV‐encoded homologue, BPLF1 and 14‐3‐3 proteins promotes the formation of the translocation complex and inhibits RIG‐I ubiquitination to block the innate immune response. Toll‐like receptors (TLRs) are activated after recognizing PAMPs, recruiting the proximal cytoplasmic Toll/IL‐1 receptor (TIR) domain‐containing adaptor proteins. Both lipoproteins and LPS are recognized on the cell surface by a heterodimer of TLR1/6 and TLR2, and TLR4, respectively. Ligand stimulation recruits MyD88 and TIRAP to TLRs, a complex of IRAKs and TRAF6 is subsequently formed, and results in NF‐κB activation. LPS induces TLR4 translocation to the endosome together with TRAM. TLR3 recognizes dsRNA in the endosomes. TLR3 and TLR4 activate TRIF‐dependent signalling, which activates NF‐kB and IRF3/7 resulting in the induction of proinflammatory cytokine genes and type I IFNs. In addition, 14‐3‐3θ can inhibit TLR2‐mediated activation of NF‐κB, but promote the activation of TLR4‐dependent transcription factors. 14‐3‐3ζ promotes the multimerization of TICAM‐1 (also known as TRIF) to form the TIC signalosome and regulate the TLR3‐TICAM‐1 signalling pathway