Human T-cell Leukemia Virus Type 1 HBZ Protein Bypasses the Targeting Function of Ubiquitination

Abstract

Human T-cell leukemia virus type 1 (HTLV-1) encodes an antisense viral gene product termed HTLV-1 basic leucine-zipper factor (HBZ). HBZ forms heterodimers with c-Jun, a member of the AP-1 family, and promotes its proteasomal degradation. Although most proteasomal substrates are targeted for degradation via conjugation of polyubiquitin chains, we show that ubiquitination is not required for HBZ-mediated proteasomal degradation of c-Jun. We demonstrate that HBZ directly interacts with both the 26 S proteasome and c-Jun and facilitates the delivery of c-Jun to the proteasome without ubiquitination. HBZ acts as a tethering factor between the 26 S proteasome and its substrate, thereby bypassing the targeting function of ubiquitination. These findings disclose a novel viral strategy to utilize the cellular proteolytic system for viral propagation. Human T-cell leukemia virus type 1 (HTLV-1) encodes an antisense viral gene product termed HTLV-1 basic leucine-zipper factor (HBZ). HBZ forms heterodimers with c-Jun, a member of the AP-1 family, and promotes its proteasomal degradation. Although most proteasomal substrates are targeted for degradation via conjugation of polyubiquitin chains, we show that ubiquitination is not required for HBZ-mediated proteasomal degradation of c-Jun. We demonstrate that HBZ directly interacts with both the 26 S proteasome and c-Jun and facilitates the delivery of c-Jun to the proteasome without ubiquitination. HBZ acts as a tethering factor between the 26 S proteasome and its substrate, thereby bypassing the targeting function of ubiquitination. These findings disclose a novel viral strategy to utilize the cellular proteolytic system for viral propagation. Protein degradation plays a variety of roles cellular the and of system as a the degradation of proteasomal substrates are with as a for the 26 S cellular that to substrates of to the with to the with the and proteasome is a proteolytic of proteolytic is the S of a S to both of the S proteasome forms the 26 S S polyubiquitin substrates and and of the the S for degradation the substrates for the are and a to the proteasome a ubiquitination not required for its degradation of degradation of and T-cell leukemia virus type HTLV-1 and T-cell leukemia virus type HTLV-1 and the of for cellular the substrates is not variety of are to utilize the system to cellular for acts as a of the to ubiquitination and degradation of the are an of viral that utilize cellular ubiquitination that the cellular proteolytic system is an for viral T-cell leukemia virus (HTLV-1) T-cell leukemia of a of cellular is with the of T-cell of the is to a the of T-cell leukemia Although promotes and of is a of the of viral is for the of are of viral that viral a novel viral HTLV-1 basic leucine-zipper factor is the of the HTLV-1 HBZ is a that a and a basic leucine-zipper its and HBZ interacts with cellular the AP-1 of and the virus to viral gene the HTLV-1 We that HBZ interacts with c-Jun, an AP-1 and its HBZ not the of c-Jun promotes its proteasomal degradation we show that ubiquitination is not required for HBZ-mediated proteasomal degradation of c-Jun. We demonstrate that HBZ directly interacts with both the 26 S proteasome and c-Jun and facilitates the delivery of c-Jun to the proteasome without ubiquitination. HBZ acts as a tethering factor between the 26 S proteasome and its substrate, thereby bypassing the targeting function of and with and a with and for for the the with with the proteasome for to and and of HBZ and c-Jun of and These as as a c-Jun, and and and to the an the the c-Jun leucine-zipper with and to a and with the and for for c-Jun and to 1 of 1 1 1 and a for the with of for with of for and and to and with the for 1 with of with and with for the with that and for 1 with of and to and with and and the system for with of 1 1 1 and a with and and with and with for and with of for with with and to with the and for and for an to the and to to the of the the to the HBZ and the the the and and to with for as the and HBZ 1 of 1 and the to a the and system a the of the HBZ We of the with of and of a the and to of virus a of of the of and and of with We the of a and and and and of that HBZ with c-Jun via leucine-zipper and targeted c-Jun for proteasomal degradation c-Jun and HBZ c-Jun c-Jun HBZ with the proteasome as HBZ the of c-Jun We the of HBZ c-Jun We the HBZ gene HBZ HBZ the of c-Jun These that HBZ c-Jun its proteasomal the of proteasomal substrates are targeted for degradation the conjugation of polyubiquitin conjugation is a variety of c-Jun is a that is we that HBZ acts as a of we HBZ promotes of c-Jun. c-Jun and HBZ and with c-Jun not we not an we to of c-Jun the of HBZ is not to c-Jun we to c-Jun the of HBZ the with of ubiquitination not to the of a of ubiquitination HBZ not the ubiquitination of AP-1 not with HBZ HBZ promotes c-Jun degradation without its not the ubiquitination of c-Jun. with of and as with as the with for with of and as the with for for HBZ-mediated of the of ubiquitination HBZ-mediated c-Jun degradation. the we a c-Jun of to We that the not c-Jun and the to with HBZ not the HBZ as as c-Jun. to that HBZ c-Jun for proteasomal degradation a promotes c-Jun degradation a HBZ promotes the degradation of c-Jun. with of the of as the with for with of and of the HBZ-mediated degradation of c-Jun is not a with of with of and of of the of of the with for 1 and for the c-Jun and c-Jun of and HBZ promotes c-Jun degradation the of a ubiquitination with 1 of the of of and of as and for an with the we a that a of with a and proteasomal degradation a the of c-Jun c-Jun is targeted for degradation and a for c-Jun c-Jun degradation a the of its degradation HBZ-mediated degradation of c-Jun not we degradation the These a that is the of degradation of c-Jun HBZ c-Jun degradation the that HBZ promotes proteasomal degradation of c-Jun a of the of HBZ-mediated proteasomal degradation. the we HBZ promotes degradation of HBZ to with and via We that HBZ with its HBZ degradation of and degradation of not the HBZ to the degradation of and HBZ to with and via and we to the we between c-Jun and HBZ not We that HBZ not the degradation of a that not with HBZ we a between HBZ and promotes degradation of that its not its HBZ promotes the degradation of that its with with without with the with of with of with for with an with an of the an with HBZ is for degradation. of c-Jun and as and with for with an and with an the with with without with an of and as and with for with an and with an with with without with an HBZ not degradation of that its with with without with an with of with of with an and with an we a c-Jun the leucine-zipper and that to with HBZ Although HBZ c-Jun not degradation of the HBZ not the degradation of not with HBZ an that the c-Jun leucine-zipper and with HBZ and HBZ These that the with HBZ is for HBZ the degradation of its we HBZ promotes degradation of that its We and and as cellular that the HBZ a with the HBZ as These and not HBZ not degradation of of HBZ for c-Jun we the of HBZ for the of c-Jun We that not the leucine-zipper as an with c-Jun, the of HBZ are for the of c-Jun. and are the of HBZ We to that to c-Jun. and These with c-Jun to HBZ not of c-Jun degradation the to c-Jun. These that the of HBZ are for the of of HBZ is for of c-Jun. the of HBZ is of the is the of c-Jun degradation with c-Jun and its of HBZ with the 26 S is that the of HBZ cellular that c-Jun degradation. We a to We a that the with the HBZ as the HBZ to to as a S proteasome the HBZ with the the to c-Jun not with the the with both and of HBZ directly interacts with the 26 S of as a for the of HBZ a as and for HBZ with with of is HBZ with as with an and with an HBZ with the 26 S with and with for with an with the HBZ with to the 26 S and S are the between HBZ and an and to and with that with not with the between HBZ and we a and HBZ with not with the These that the of HBZ with the proteasomal and that with the of HBZ with not HBZ interacts with of we of the proteasome with of the proteasomal with not with its and are that the of the S and are of the S of both the S and S with that HBZ interacts with the 26 S proteasome the of HBZ and the 26 S proteasome a findings that HBZ interacts with the 26 S proteasome and c-Jun via its and that HBZ acts as a tethering factor between c-Jun and the 26 S thereby delivery of c-Jun to the proteasome a that the HTLV-1 encodes an of HBZ termed We the HBZ to c-Jun. c-Jun degradation the with the proteasome the of the between HBZ and the 26 S proteasome c-Jun to c-Jun promotes degradation of c-Jun with of and of with with the proteasome with of and with with an and with an of and HBZ are and to utilize the system for propagation. and as of to ubiquitination and degradation of the virus acts as an that a cellular for proteasomal degradation a are an of viral that utilize cellular ubiquitination to cellular the the to proteasomal degradation of without its ubiquitination the of is a of and to a the of cellular we demonstrate that the HTLV-1 HBZ promotes degradation of c-Jun, a cellular a HBZ-mediated degradation of c-Jun proteasome HBZ to c-Jun ubiquitination. HBZ a c-Jun for ubiquitination. a to HBZ-mediated c-Jun degradation. c-Jun degradation HBZ the that HBZ promotes c-Jun degradation a the of HBZ c-Jun for proteasomal the to a of thereby its degradation for the 26 S proteasome promotes degradation the of with the 26 S degradation of and is to the S These are directly the of the S proteasome the to degradation of and a directly with both and the S proteasome and facilitates S S tethering function of is to HBZ-mediated c-Jun degradation. we that HBZ interacts with the 26 S proteasome and c-Jun via its and we that are for c-Jun These that HBZ acts as a tethering factor between c-Jun and the 26 S thereby the delivery of c-Jun to the proteasome without is the of HBZ-mediated c-Jun the viral AP-1 is Although AP-1 to T-cell AP-1 HBZ AP-1 we that HBZ promotes degradation of cellular and that are the HTLV-1 viral are of the is for viral propagation. as a of viral HBZ a and HTLV-1 we disclose a viral strategy to utilize the proteolytic for viral propagation. HBZ acts as a tethering factor between the 26 S proteasome and its substrate, thereby the targeting function of ubiquitination. findings the cellular proteasomal degradation is that tethering between the proteasome and its is a cellular proteolytic We that the degradation show the of degradation cellular Protein degradation plays a variety of roles cellular the and of system as a the degradation of proteasomal substrates are with as a for the 26 S cellular that to substrates of to the with to the with the and proteasome is a proteolytic of proteolytic is the S of a S to both of the S proteasome forms the 26 S S polyubiquitin substrates and and of the the S for degradation the substrates for the are and a to the proteasome a ubiquitination not required for its degradation of degradation of and T-cell leukemia virus type HTLV-1 and T-cell leukemia virus type HTLV-1 and the of for cellular the substrates is not variety of are to utilize the system to cellular for acts as a of the to ubiquitination and degradation of the are an of viral that utilize cellular ubiquitination that the cellular proteolytic system is an for viral propagation. Human T-cell leukemia virus (HTLV-1) T-cell leukemia of a of cellular is with the of T-cell of the is to a the of T-cell leukemia Although promotes and of is a of the of viral is for the of are of viral that viral a novel viral HTLV-1 basic leucine-zipper factor is the of the HTLV-1 HBZ is a that a and a basic leucine-zipper its and HBZ interacts with cellular the AP-1 of and the virus to viral gene the HTLV-1 We that HBZ interacts with c-Jun, an AP-1 and its HBZ not the of c-Jun promotes its proteasomal degradation we show that ubiquitination is not required for HBZ-mediated proteasomal degradation of c-Jun. We demonstrate that HBZ directly interacts with both the 26 S proteasome and c-Jun and facilitates the delivery of c-Jun to the proteasome without ubiquitination. 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These that the of HBZ are for the of of HBZ is for of c-Jun. the of HBZ is of the is the of c-Jun degradation with c-Jun and its of HBZ with the 26 S is that the of HBZ cellular that c-Jun degradation. 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HBZ the degradation of its we HBZ promotes degradation of that its We and and as cellular that the HBZ a with the HBZ as These and not HBZ not degradation of of HBZ for c-Jun we the of HBZ for the of c-Jun We that not the leucine-zipper as an with c-Jun, the of HBZ are for the of c-Jun. and are the of HBZ We to that to c-Jun. and These with c-Jun to HBZ not of c-Jun degradation the to c-Jun. These that the of HBZ are for the of c-Jun. of HBZ with the 26 S is that the of HBZ cellular that c-Jun degradation. We a to We a that the with the HBZ as the HBZ to to as a S proteasome the HBZ with the the to c-Jun not with the the with both and We the between HBZ and an and to and with that with not with the between HBZ and we a and HBZ with not with the These that the of HBZ with the proteasomal and that with the of c-Jun. Although HBZ with not HBZ interacts with of we of the proteasome with of the proteasomal with not with its and are that the of the S and are of the S of both the S and S with that HBZ interacts with the 26 S proteasome the of HBZ and the 26 S proteasome a findings that HBZ interacts with the 26 S proteasome and c-Jun via its and that HBZ acts as a tethering factor between c-Jun and the 26 S thereby delivery of c-Jun to the proteasome a that the HTLV-1 encodes an of HBZ termed We the HBZ to c-Jun. c-Jun degradation the with the proteasome the of the between HBZ and the 26 S proteasome c-Jun to utilize the system for propagation. and as of to ubiquitination and degradation of the virus acts as an that a cellular for proteasomal degradation a are an of viral that utilize cellular ubiquitination to cellular the the to proteasomal degradation of without its ubiquitination the of is a of and to a the of cellular we demonstrate that the HTLV-1 HBZ promotes degradation of c-Jun, a cellular a HBZ-mediated degradation of c-Jun proteasome HBZ to c-Jun ubiquitination. HBZ a c-Jun for ubiquitination. a to HBZ-mediated c-Jun degradation. c-Jun degradation HBZ the that HBZ promotes c-Jun degradation a the of HBZ c-Jun for proteasomal the to a of thereby its degradation for the 26 S proteasome promotes degradation the of with the 26 S degradation of and is to the S These are directly the of the S proteasome the to degradation of and a directly with both and the S proteasome and facilitates S S tethering function of is to HBZ-mediated c-Jun degradation. we that HBZ interacts with the 26 S proteasome and c-Jun via its and we that are for c-Jun These that HBZ acts as a tethering factor between c-Jun and the 26 S thereby the delivery of c-Jun to the proteasome without is the of HBZ-mediated c-Jun the viral AP-1 is Although AP-1 to T-cell AP-1 HBZ AP-1 we that HBZ promotes degradation of cellular and that are the HTLV-1 viral are of the is for viral propagation. as a of viral HBZ a and HTLV-1 we disclose a viral strategy to utilize the proteolytic for viral propagation. HBZ acts as a tethering factor between the 26 S proteasome and its substrate, thereby the targeting function of ubiquitination. findings the cellular proteasomal degradation is that tethering between the proteasome and its is a cellular proteolytic We that the degradation show the of degradation cellular to utilize the system for propagation. and as of to ubiquitination and degradation of the virus acts as an that a cellular for proteasomal degradation a are an of viral that utilize cellular ubiquitination to cellular the the to proteasomal degradation of without its ubiquitination the of is a of and to a the of cellular we demonstrate that the HTLV-1 HBZ promotes degradation of c-Jun, a cellular a HBZ-mediated degradation of c-Jun proteasome HBZ to c-Jun ubiquitination. HBZ a c-Jun for ubiquitination. a to HBZ-mediated c-Jun degradation. c-Jun degradation HBZ the that HBZ promotes c-Jun degradation a the of HBZ c-Jun for proteasomal the to a of thereby its degradation for the 26 S proteasome promotes degradation the of with the 26 S degradation of and is to the S These are directly the of the S proteasome the to degradation of and a directly with both and the S proteasome and facilitates S S tethering function of is to HBZ-mediated c-Jun degradation. we that HBZ interacts with the 26 S proteasome and c-Jun via its and we that are for c-Jun These that HBZ acts as a tethering factor between c-Jun and the 26 S thereby the delivery of c-Jun to the proteasome without ubiquitination. is the of HBZ-mediated c-Jun the viral AP-1 is Although AP-1 to T-cell AP-1 HBZ AP-1 we that HBZ promotes degradation of cellular and that are the HTLV-1 viral are of the is for viral propagation. as a of viral HBZ a and HTLV-1 we disclose a viral strategy to utilize the proteolytic for viral propagation. HBZ acts as a tethering factor between the 26 S proteasome and its substrate, thereby the targeting function of ubiquitination. findings the cellular proteasomal degradation is that tethering between the proteasome and its is a cellular proteolytic We that the degradation show the of degradation cellular We for the and for the