PJA1 Coordinates with the SMC5/6 Complex To Restrict DNA Viruses and Episomal Genes in an Interferon-Independent Manner

Abstract

DNA viruses, including hepatitis B virus and herpes simplex virus, induce a series of immune responses in the host and lead to human public health concerns worldwide. In addition to cytokines in the cytoplasm, restriction of viral DNA in the nucleus is an important approach of host immunity. However, the mechanism of foreign DNA recognition and restriction in the cell nucleus is largely unknown. This work demonstrates that an important cellular factor (PJA1) suppresses DNA viruses and transfected plasmids independent of type I and II interferon (IFN) pathways. Instead, PJA1 interacts with the chromosome maintenance complex (SMC5/6), facilitates the complex to recognize and bind viral and episomal DNAs, and recruits DNA topoisomerases to restrict the foreign molecules. These results reveal a distinct mechanism underlying the silencing of viral and episomal invaders in the cell nuclei and suggest that PJA1 acts as a potential agent to prevent infectious and inflammatory diseases.

The SMC5/6 Complex Represses the Replicative Program of High-Risk Human Papillomavirus Type 31

“…Previously, SMC5/6 has been shown to inhibit the transcription of HBV [ 8 , 9 , 10 , 11 ] and HSV-1 [ 11 ]. We questioned whether these antiviral functions of SMC6 and its interactions with HPV E2 indicated that SMC5/6 functions as a repressor of HPV-31 replication or transcription.…”

“…SMC6 has been shown to associate with nuclear episomal HBV cccDNA [ 8 ] and HSV-1 DNA [ 11 ], but how SMC5/6 localizes to viral DNA remains unclear. An SMC6 association with HPV genomes has not been reported.…”

“…SMC5/6 associates with host chromatin to mediate homologous recombination DNA repair, rescue stalled replication forks [ 30 ], and topologically entrap extrachromosomal DNA [ 31 ]. Additionally, SMC5/6 has been shown to associate with hepatitis B [ 8 , 11 ] and herpes simplex-1 [ 11 ] viral episomes. The purported localization of SMC6 to viral DNA and its association with E2 led us to speculate that SMC6 may be present on episomal HPV-31 genomes.…”

“…SMC5/6 is required for multiple cellular functions, such as host DNA damage repair by homologous recombination [ 4 ], and is essential for cell viability [ 7 ]. Recently, antiviral roles have been described for SMC5/6, whereby SMC5/6 restricts transcription of hepatitis B [ 8 , 9 , 10 , 11 ] and herpes simplex-1 (HSV-1) viruses [ 11 ]. SMC5/6 has also been found to interact with both high- and low-risk HPV E2 proteins and is purportedly involved in HPV genome maintenance [ 12 ], but the significance of SMC5/6 interactions with E2 and its role during the HPV life cycle is not fully understood.…”

SOX2 Represses Hepatitis B Virus Replication by Binding to the Viral EnhII/Cp and Inhibiting the Promoter Activation

“…The glycine at the final concentration of 125 mM was added for 5 min to terminate cross-linking. The precipitated DNA was purified according to the protocol described in our previous study [19]. The DNA was detected by agarose gel electrophoresis and qRT-PCR.…”