The Nuclear Pore Complex Is a Key Target of Viral Proteases to Promote Viral Replication

Abstract

Various viruses alter nuclear pore complex (NPC) integrity to access the nuclear content favoring their replication. Alteration of the nuclear pore complex has been observed not only in viruses that replicate in the nucleus but also in viruses with a cytoplasmic replicative cycle. In this last case, the alteration of the NPC can reduce the transport of transcription factors involved in the immune response or mRNA maturation, or inhibit the transport of mRNA from the nucleus to the cytoplasm, favoring the translation of viral mRNAs or allowing access to nuclear factors necessary for viral replication. In most cases, the alteration of the NPC is mediated by viral proteins, being the viral proteases, one of the most critical groups of viral proteins that regulate these nucleus–cytoplasmic transport changes. This review focuses on the description and discussion of the role of viral proteases in the modification of nucleus–cytoplasmic transport in viruses with cytoplasmic replicative cycles and its repercussions in viral replication.

Genetic Associations and Differential mRNA Expression Levels of Host Genes Suggest a Viral Trigger for Endemic Pemphigus Foliaceus

“…Many viruses hijack the NPC to regulate the nucleocytoplasmic trafficking of viral and host macromolecules, promoting viral replication and affecting host cell pathways to evade antiviral responses [ 91 ]. Proteases of flaviviruses (such as DENV, ZIKV, and YFV) and picornaviruses degrade nucleoporins to inhibit the nuclear import/export of host molecules involved in the immune response [ 92 , 93 ]. TPR is one of the NPC proteins degraded by a ZIKV protease [ 93 ] and may promote HIV infection by ensuring that the chromatin environment near the nuclear pore is active, with implications for the preferential integration of HIV into actively transcribed genes [ 94 ].…”

“…Proteases of flaviviruses (such as DENV, ZIKV, and YFV) and picornaviruses degrade nucleoporins to inhibit the nuclear import/export of host molecules involved in the immune response [ 92 , 93 ]. TPR is one of the NPC proteins degraded by a ZIKV protease [ 93 ] and may promote HIV infection by ensuring that the chromatin environment near the nuclear pore is active, with implications for the preferential integration of HIV into actively transcribed genes [ 94 ]. On the other hand, HIV-1 infection can be inhibited via a mechanism that involves targeted repression of NUP50 [ 95 ].…”

Quantitative temporal analysis of modified vaccinia Ankara, the monkeypox and smallpox vaccine

“…The innate immune response to virus infection requires an intact NPC to mediate nucleocytoplasmic transport of transcription factors and mRNAs and therefore, downregulation/degradation of NPC proteins may be a viral immune evasion strategy. Although some viral proteases inactivate nucleoporins (NUPs) by cleavage 37 , NUP abundance did not vary substantially during infection by multiple human pathogenic viruses, such as human cytomegalovirus 2 , herpes simplex virus type 1 16 , influenza A virus 38 , Epstein-Barr virus 39 , SARS-CoV-2 40 and HIV 41 . Therefore, to our knowledge, MVA is the first virus reported to downregulate/degrade NUPs.…”

Potential Role of Flavivirus NS2B-NS3 Proteases in Viral Pathogenesis and Anti-flavivirus Drug Discovery Employing Animal Cells and Models: A Review

“…The flaviviral proteins are known to interact with the NPC and the associated proteins to disrupt the nucleocytoplasmic trafficking, and to gain entry into the nucleus [139]. The latter strategy may be adopted so that the NPC changes result in the reduced trafficking of mRNA or other transcription factors, which can result in a suppressed immune response against that viral infection [143]. Recent studies have also demonstrated the ability of flaviviral NS2B-NS3 to affect the integrity and distribution of nucleoporins (Nups).…”