Herpesviruses assemble and fill their capsids in the infected cell nucleus, and must then move this enormous macromolecular assembly across the nuclear membrane and into the cytoplasm. Doing so is a complex, multi-ste...Herpesviruses assemble and fill their capsids in the infected cell nucleus, and must then move this enormous macromolecular assembly across the nuclear membrane and into the cytoplasm. Doing so is a complex, multi-step process that involves envelopment of the capsid at the inner nuclear membrane and de-envelopment by fusion with the outer nuclear membrane. This process is orchestrated by viral proteins, but requires the modification of cellular structures and mechanisms including the nuclear lamina. In this review I summarize recent research on the mechanism of nuclear envelopment and the viral and cellular systems involved in its execution.展开更多
Circulation of mature lymphocytes between blood and secondary lymphoid tissues plays a central role in the immune system. Homing of lymphocytes from blood into secondary lymphoid tissues beyond high endothelial venule...Circulation of mature lymphocytes between blood and secondary lymphoid tissues plays a central role in the immune system. Homing of lymphocytes from blood into secondary lymphoid tissues beyond high endothelial venules is highly dependent on the interaction between the chemokines CCL19, CCL21, CXCL12, and CXCL13, and their receptors CCR7, CXCR4 and CXCR5. However, the molecular mechanism（s） of lymphocyte egress from secondary lymphoid tissues to lymph remained unclear. We have found a new class of immunomodulator, FTY720 by chemical modification of vegetative wasp-derived natural product, ISP-I （myriocin）. FTY720 has been shown to be highly effective in experimental allograft and autoimmune disease models. A striking feature of FTY720 is the induction of a marked decrease in peripheral blood lymphocytes at doses that show immunomodulating activity in these models. The reduction of circulating lymphocytes by FTY720 is caused by sequestration of lymphocytes into secondary lymphoid tissues and thymus. FTY720 is rapidly converted to （S）-enantiomer of FTY720-phosphate [（S）-FTY720-P] by sphingosine kinase 2 in vivo. （S）-FTY720-P acting as a potent agonist of S1P receptor type 1 （S1P1）, induces long-term down-regulation of S1P1 on lymphocytes, and thereby inhibits the migration of lymphocytes toward S1P. Thus, it is presumed that FTY720-induced lymphocyte sequestration is due to the inhibition of S1P/S1P1-dependent lymphocyte egress from secondary lymphoid tissues and thymus by its active metabolite （S）-FTY720-P. Throughout the analysis of the mechanism of action of FTY720, it is clarified that S1P/S1P1 interaction plays an important role for lymphocyte egress from secondary lymphoid tissues and thymus.展开更多
Morphogenesis and maturation of viral particles is an essential step of viral replication.An infectious herpesviral particle has a multilayered architecture,and contains a large DNA genome,a capsid shell,a tegument an...Morphogenesis and maturation of viral particles is an essential step of viral replication.An infectious herpesviral particle has a multilayered architecture,and contains a large DNA genome,a capsid shell,a tegument and an envelope spiked with glycoproteins.Unique to herpesviruses,tegument is a structure that occupies the space between the nucleocapsid and the envelope and contains many virus encoded proteins called tegument proteins.Historically the tegument has been described as an amorphous structure,but increasing evidence supports the notion that there is an ordered addition of tegument during virion assembly,which is consistent with the important roles of tegument proteins in the assembly and egress of herpesviral particles.In this review we first give an overview of the herpesvirus assembly and egress process.We then discuss the roles of selected tegument proteins in each step of the process,i.e.,primary envelopment,deenvelopment,secondary envelopment and transport of viral particles.We also suggest key issues that should be addressed in the near future.展开更多
Many viruses,enveloped or non-enveloped,remodel host membrane structures for their replication,assembly and escape from host cells.Herpesviruses are important human pathogens and cause many diseases.As large enveloped...Many viruses,enveloped or non-enveloped,remodel host membrane structures for their replication,assembly and escape from host cells.Herpesviruses are important human pathogens and cause many diseases.As large enveloped DNA viruses,herpesviruses undergo several complex steps to complete their life cycles and produce infectious progenies.Firstly,herpesvirus assembly initiates in the nucleus,producing nucleocapsids that are too large to cross through the nuclear pores.Nascent nucleocapsids instead bud at the inner nuclear membrane to form primary enveloped virions in the perinuclear space followed by fusion of the primary envelopes with the outer nuclear membrane,to translocate the nucleocapsids into the cytoplasm.Secondly,nucleocapsids obtain a series of tegument proteins in the cytoplasm and bud into vesicles derived from host organelles to acquire viral envelopes.The vesicles are then transported to and fuse with the plasma membrane to release the mature virions to the extracellular space.Therefore,at least two budding and fusion events take place at cellular membrane structures during herpesviruses assembly and egress,which induce membrane deformations.In this review,we describe and discuss how herpesviruses exploit and remodel host membrane structures to assemble and escape from the host cell.展开更多
Autographa californica multiple nucleopolyhedrovirus(Ac MNPV)orf13(ac13)is a conserved gene in all sequenced alphabaculoviruses.However,its function in the viral life cycle remains unknown.In this study,we found that ...Autographa californica multiple nucleopolyhedrovirus(Ac MNPV)orf13(ac13)is a conserved gene in all sequenced alphabaculoviruses.However,its function in the viral life cycle remains unknown.In this study,we found that ac13 was a late gene and that the encoded protein,bearing a putative nuclear localization signal motif,colocalized with the nuclear lamina.Deletion of ac13 did not affect viral genome replication,nucleocapsid assembly or occlusion body(OB)formation,but reduced virion budding from infected cells by approximately 400-fold compared with the wild-type virus.Deletion of ac13 substantially impaired the egress of nucleocapsids from the nucleus to the cytoplasm,while the OB morphogenesis was unaffected.Taken together,our results indicated that ac13 was required for efficient nuclear egress of nucleocapsids during virion budding,but was dispensable for OB formation.展开更多
基金supported by US Public health Service award AI 41478
文摘Herpesviruses assemble and fill their capsids in the infected cell nucleus, and must then move this enormous macromolecular assembly across the nuclear membrane and into the cytoplasm. Doing so is a complex, multi-step process that involves envelopment of the capsid at the inner nuclear membrane and de-envelopment by fusion with the outer nuclear membrane. This process is orchestrated by viral proteins, but requires the modification of cellular structures and mechanisms including the nuclear lamina. In this review I summarize recent research on the mechanism of nuclear envelopment and the viral and cellular systems involved in its execution.
文摘Circulation of mature lymphocytes between blood and secondary lymphoid tissues plays a central role in the immune system. Homing of lymphocytes from blood into secondary lymphoid tissues beyond high endothelial venules is highly dependent on the interaction between the chemokines CCL19, CCL21, CXCL12, and CXCL13, and their receptors CCR7, CXCR4 and CXCR5. However, the molecular mechanism（s） of lymphocyte egress from secondary lymphoid tissues to lymph remained unclear. We have found a new class of immunomodulator, FTY720 by chemical modification of vegetative wasp-derived natural product, ISP-I （myriocin）. FTY720 has been shown to be highly effective in experimental allograft and autoimmune disease models. A striking feature of FTY720 is the induction of a marked decrease in peripheral blood lymphocytes at doses that show immunomodulating activity in these models. The reduction of circulating lymphocytes by FTY720 is caused by sequestration of lymphocytes into secondary lymphoid tissues and thymus. FTY720 is rapidly converted to （S）-enantiomer of FTY720-phosphate [（S）-FTY720-P] by sphingosine kinase 2 in vivo. （S）-FTY720-P acting as a potent agonist of S1P receptor type 1 （S1P1）, induces long-term down-regulation of S1P1 on lymphocytes, and thereby inhibits the migration of lymphocytes toward S1P. Thus, it is presumed that FTY720-induced lymphocyte sequestration is due to the inhibition of S1P/S1P1-dependent lymphocyte egress from secondary lymphoid tissues and thymus by its active metabolite （S）-FTY720-P. Throughout the analysis of the mechanism of action of FTY720, it is clarified that S1P/S1P1 interaction plays an important role for lymphocyte egress from secondary lymphoid tissues and thymus.
基金supported by the“One Hundred Talents Program”the Chinese Academy of Sciences and the National Protein Science Project(No.2006CB910901)from the Ministry of Science and Technology.
文摘Morphogenesis and maturation of viral particles is an essential step of viral replication.An infectious herpesviral particle has a multilayered architecture,and contains a large DNA genome,a capsid shell,a tegument and an envelope spiked with glycoproteins.Unique to herpesviruses,tegument is a structure that occupies the space between the nucleocapsid and the envelope and contains many virus encoded proteins called tegument proteins.Historically the tegument has been described as an amorphous structure,but increasing evidence supports the notion that there is an ordered addition of tegument during virion assembly,which is consistent with the important roles of tegument proteins in the assembly and egress of herpesviral particles.In this review we first give an overview of the herpesvirus assembly and egress process.We then discuss the roles of selected tegument proteins in each step of the process,i.e.,primary envelopment,deenvelopment,secondary envelopment and transport of viral particles.We also suggest key issues that should be addressed in the near future.
基金the Ministry of Science and Technology(National Key R&D Program of China,No.2016YFA0502101)the National Natural Science Foundation of China(No.81630059 and 81325012).
文摘Many viruses,enveloped or non-enveloped,remodel host membrane structures for their replication,assembly and escape from host cells.Herpesviruses are important human pathogens and cause many diseases.As large enveloped DNA viruses,herpesviruses undergo several complex steps to complete their life cycles and produce infectious progenies.Firstly,herpesvirus assembly initiates in the nucleus,producing nucleocapsids that are too large to cross through the nuclear pores.Nascent nucleocapsids instead bud at the inner nuclear membrane to form primary enveloped virions in the perinuclear space followed by fusion of the primary envelopes with the outer nuclear membrane,to translocate the nucleocapsids into the cytoplasm.Secondly,nucleocapsids obtain a series of tegument proteins in the cytoplasm and bud into vesicles derived from host organelles to acquire viral envelopes.The vesicles are then transported to and fuse with the plasma membrane to release the mature virions to the extracellular space.Therefore,at least two budding and fusion events take place at cellular membrane structures during herpesviruses assembly and egress,which induce membrane deformations.In this review,we describe and discuss how herpesviruses exploit and remodel host membrane structures to assemble and escape from the host cell.
基金supported by the National Key Research and Development Program of China(2017YFD0201206)the WIV “One-Three-Five”strategic program(Y602111SA1 to XS)。
文摘Autographa californica multiple nucleopolyhedrovirus(Ac MNPV)orf13(ac13)is a conserved gene in all sequenced alphabaculoviruses.However,its function in the viral life cycle remains unknown.In this study,we found that ac13 was a late gene and that the encoded protein,bearing a putative nuclear localization signal motif,colocalized with the nuclear lamina.Deletion of ac13 did not affect viral genome replication,nucleocapsid assembly or occlusion body(OB)formation,but reduced virion budding from infected cells by approximately 400-fold compared with the wild-type virus.Deletion of ac13 substantially impaired the egress of nucleocapsids from the nucleus to the cytoplasm,while the OB morphogenesis was unaffected.Taken together,our results indicated that ac13 was required for efficient nuclear egress of nucleocapsids during virion budding,but was dispensable for OB formation.
