The suppression of apoptosis by α-herpesvirus

Abstract

Apoptosis, an important innate immune mechanism that eliminates pathogen-infected cells, is primarily triggered by two signalling pathways: the death receptor pathway and the mitochondria-mediated pathway. However, many viruses have evolved various strategies to suppress apoptosis by encoding anti-apoptotic factors or regulating apoptotic signalling pathways, which promote viral propagation and evasion of the host defence. During its life cycle, α-herpesvirus utilizes an elegant multifarious anti-apoptotic strategy to suppress programmed cell death. This progress article primarily focuses on the current understanding of the apoptosis-inhibition mechanisms of α-herpesvirus anti-apoptotic genes and their expression products and discusses future directions, including how the anti-apoptotic function of herpesvirus could be targeted therapeutically.

Figure 1

Overview of the types of herpesvirus genomes and the structure of virion. (I) The type A genomes (e.g., EHV-2) consist of a unique (U) region that is flanked by a direct terminal repeat (TR). The type B structure (e.g., Kaposi's sarcoma-associated herpesvirus) also consists of a U region flanked by variable numbers of TRs. The type C genomes (e.g., Epstein-Barr virus) harbour variable numbers of terminal sequences and an internal direct repeat that is unrelated to the TR and splits the U region into two unique regions (U_L and U_s). The type D (e.g., PRV) and E (e.g., HSV-1) genomes contain U_L and U_S regions that are each flanked by terminal and internal inverted repeats (TR_L/IR_L and IR_S/TR_S). The TR_L/IR_L regions are very short in some type D genomes (e.g., VZV), whereas they are longer in viruses with class E genomes. In the type E structure, there is also a terminal direct repeat of hundreds of base pairs that is known as the a sequence. Moreover, an inverted copy, known as the a' sequence, is present internally. (II) The structure consists of four elements: (1) a core containing the viral dsDNA; (2) a T=16 icosahedral capsid encircling the core; (3) an amorphous protein layer called the tegument that surrounds the capsid; and (4) an outer lipid envelope (some inspiration came from these articles^{, , , ,} )

Figure 2

The lytic replication cycle of herpesviruses: (1) entry into the cell, (2) transfer of the capsids to the nucleus, (3) viral DNA replication, (4) capsid assembly, (5) egress from the nucleus, (6) maturation and envelopment of viral particles in the cytoplasm and (7) exocytosis of mature virions (some inspiration came from these articles^{, , , , ,} )

Figure 3

The extrinsic apoptosis pathway. (a) Fas and DR4/5 are activated by the binding of their respective ligands FasL and TRAIL; the receptors then bind to FADD via the death domain (DD). Then, the death effector domain (DED) of FADD binds to procaspase-8/10, forming the death-inducing signalling complex (DISC) to facilitate the autoproteolytic cleavage of procaspase-8/10, which induces the activation of the caspase cascade and ultimately results in apoptosis. (b) In particular cells, activated caspase-8 cleaves the pro-apoptotic protein Bid to create truncated Bid (tBid), and this results in the activation of the mitochondria-mediated apoptotic signalling pathway. (c) TNFR1, EDAR and DR3/6 are activated by the binding of their respective ligands. TNFR1 recruits TRADD, an adaptor protein that binds to TNF receptor-associated factors (TRAFs), receptor-interacting protein kinase (RIP1) and cellular inhibitor of apoptosis (cIAPs), forming the initial membrane pro-survival complex (complex I), which stimulates the MAPK/JNK and NF-κB pathways to facilitate cell survival or apoptosis. (d) Complex I forms two types of cytoplasmic apoptotic complexes, TRADD-dependent complex IIA and RIP1-dependent complex IIB, which activate caspase-8, thus initiating apoptosis (some inspiration came from these articles^{, , , , ,} )

Figure 4

The intrinsic apoptosis pathway. The intrinsic apoptotic pathway is triggered by intracellular stimuli. (a) Intracellular apoptotic stimuli upregulate the pro-apoptotic Bcl-2 family of proteins, such as Bax, Bid, Bak and Bad, leading to the mitochondrial release of cytochrome C, which binds to Apaf-1. The replacement of ADP by dATP/ATP in Apaf-1 triggers the formation of a heptameric apoptosome, which assembles with procaspase-9 to form the holo-apoptosome. The Apaf-1 apoptosome catalyses the cleavage and activation of procaspase-9, which triggers the caspase cascade, and the activation of caspase-3 and caspase-7 leads to eventual apoptosis. (b) Under ER stress, three upstream signalling proteins – IRE1, PERK and ATF6 – are activated, thus leading to a cascade of activity that induces apoptosis. (b1) The ER releases Ca²⁺ from the ER lumen into the cytoplasm, which triggers apoptosis by activating the calcium-sensing kinase CaMKII. Then, CaMKII activates procaspase, which in turn triggers caspase cascade activation. (b2) The prolonged activation of IRE1 can promote apoptosis. Phosphorylated IRE1 recruits TRAF2 (TNF receptor-associated factor 2) and triggers a cascade of phosphorylation events, such as the activation of ASK1 (apoptosis signalling kinase 1), which ultimately phosphorylates and activates JNK. Then, JNK phosphorylation activates pro-apoptotic Bim and blocks anti-apoptotic Bcl-2. (b3) The homomultimerization and autophosphorylation of PERK leads to eIF-2α (eukaryotic translation initiation factor 2α) phosphorylation, which increases the translation of ATF4 (activating transcription factor-4). Then, ATF4 upregulates the expression of CHOP (C/EBP-homologous protein), which promotes apoptosis through two of the major cell death pathways – the IP3R–Ca²⁺–CaMKII pathway and the Bcl-2 family member pathway (some inspiration came from these articles^{, , , , ,} )

Figure 5

The anti-apoptotic pathway of LAT. The main domain of the LAT gene is contained in the first 1.5 kb. LAT can inhibit apoptosis by interacting with the following pathways: (a) LAT stabilizes the levels of total and phosphorylated AKT protein, which phosphorylates and inactivates the pro-apoptotic proteins Bad, Bax and caspase-9 to ultimately regulate caspase-3 activation and block apoptosis; (b) LAT cooperates with RIG-1 to promote NF-κB-dependent transcription to interfere with apoptosis and benefit cell survival; and (c) LAT substitutes for the function of c-FLIP, which is an inhibitor of caspase-8-mediated apoptosis