UBX domain proteins: major regulators of the AAA ATPase Cdc48/p97

Abstract

Abstract. The highly conserved AAA ATPase Cdc48/ p97 acts on ubiquitylated substrate proteins in cellular processes as diverse as the fusion of homotypic membranes and the degradation of misfolded proteins. The Ubiquitin regulatory X (UBX) domaincontaining proteins constitute the so far largest family of Cdc48/p97 cofactors. UBX proteins are involved in substrate recruitment to Cdc48/p97 and in the temporal and spatial regulation of its activity. In combination with UBX-like proteins and other cofactors, they can assemble into a large variety of Cdc48/p97-cofactor complexes possessing distinct cellular functions. This review gives an overview of the different subfamilies of UBX proteins and their functions, and discusses general principles of Cdc48/p97 regulation by these cofactors.

NEDD8 links cullin-RING ubiquitin ligase function to the p97 pathway

“…Ubx5, like UBXD7, contains UBA, UAS, UBX, and UIM domains (Supplementary Fig. 5a and b), which is consistent with the suggestion that it is the yeast equivalent of mammalian UBXD7 21 . Moreover, Ubx5 binds yeast Cul3 20 , which associates with ElonginC and therefore is functionally most closely related to human CUL2/CUL5 22 .…”

NEDD8 links cullin-RING ubiquitin ligase function to the p97 pathway

“…Ubx5, like UBXD7, contains UBA, UAS, UBX, and UIM domains (Supplementary Fig. 5a and b), which is consistent with the suggestion that it is the yeast equivalent of mammalian UBXD7 21 . Moreover, Ubx5 binds yeast Cul3 20 , which associates with ElonginC and therefore is functionally most closely related to human CUL2/CUL5 22 .…”

Protection of Armadillo/β-Catenin by Armless, a Novel Positive Regulator of Wingless Signaling

“…Our studies are consistent with earlier work that showed that the human ortholog of Ter94, p97, interacts with UBXN6 [42]. Ter94/p97/Cdc48 is a conserved and highly abundant AAA ATPase that was found to associate with SCF/Slimb/βTRCP E3 Ub ligases or proteasomal shuttle factors to mediate UPS-mediated protein degradation ([33],[42]–[45]; reviewed in [6],[34]). Specifications of the diverse activities of Ter94/p97 and the fate of its substrates are mainly exerted by UBX domain protein co-factors, which eventually either promote or hinder p97's function in protein turnover; an example of the latter involves the dissociation of the SCF/Slimb/βTRCP E3 Ub ligase complex, eventually leading to its inactivation [45].…”

Ubiquitin- and ATP-dependent unfoldase activity of P97/VCP•NPLOC4•UFD1L is enhanced by a mutation that causes multisystem proteinopathy

“…In agreement with prior work, UN bridges the interaction of substrates with p97 (25,48). However, p97 also associates with other adaptor proteins, some of which (e.g., UBXN7) can cobind with UN and others (e.g., NSFL1C) of which bind in a mutually exclusive manner (36,37,46,90,91). Although there are examples of processes that require UN and an additional adaptor (42,92), in general, it is unclear whether the different adaptors work in different pathways, or work sequentially, together, or in opposition to one another in the same pathway.…”

NEDD8 links cullin-RING ubiquitin ligase function to the p97 pathway

“…Ubx5, like UBXD7, contains UBA, UAS, UBX, and UIM domains (Supplementary Fig. 5a and b), which is consistent with the suggestion that it is the yeast equivalent of mammalian UBXD7 21 . Moreover, Ubx5 binds yeast Cul3 20 , which associates with ElonginC and therefore is functionally most closely related to human CUL2/CUL5 22 .…”

Protection of Armadillo/β-Catenin by Armless, a Novel Positive Regulator of Wingless Signaling

“…Our studies are consistent with earlier work that showed that the human ortholog of Ter94, p97, interacts with UBXN6 [42]. Ter94/p97/Cdc48 is a conserved and highly abundant AAA ATPase that was found to associate with SCF/Slimb/βTRCP E3 Ub ligases or proteasomal shuttle factors to mediate UPS-mediated protein degradation ([33],[42]–[45]; reviewed in [6],[34]). Specifications of the diverse activities of Ter94/p97 and the fate of its substrates are mainly exerted by UBX domain protein co-factors, which eventually either promote or hinder p97's function in protein turnover; an example of the latter involves the dissociation of the SCF/Slimb/βTRCP E3 Ub ligase complex, eventually leading to its inactivation [45].…”

Ubiquitin- and ATP-dependent unfoldase activity of P97/VCP•NPLOC4•UFD1L is enhanced by a mutation that causes multisystem proteinopathy

“…In agreement with prior work, UN bridges the interaction of substrates with p97 (25,48). However, p97 also associates with other adaptor proteins, some of which (e.g., UBXN7) can cobind with UN and others (e.g., NSFL1C) of which bind in a mutually exclusive manner (36,37,46,90,91). Although there are examples of processes that require UN and an additional adaptor (42,92), in general, it is unclear whether the different adaptors work in different pathways, or work sequentially, together, or in opposition to one another in the same pathway.…”

NEDD8 links cullin-RING ubiquitin ligase function to the p97 pathway

“…Ubx5, like UBXD7, contains UBA, UAS, UBX, and UIM domains (Supplementary Fig. 5a and b), which is consistent with the suggestion that it is the yeast equivalent of mammalian UBXD7 21 . Moreover, Ubx5 binds yeast Cul3 20 , which associates with ElonginC and therefore is functionally most closely related to human CUL2/CUL5 22 .…”

Protection of Armadillo/β-Catenin by Armless, a Novel Positive Regulator of Wingless Signaling

“…Our studies are consistent with earlier work that showed that the human ortholog of Ter94, p97, interacts with UBXN6 [42]. Ter94/p97/Cdc48 is a conserved and highly abundant AAA ATPase that was found to associate with SCF/Slimb/βTRCP E3 Ub ligases or proteasomal shuttle factors to mediate UPS-mediated protein degradation ([33],[42]–[45]; reviewed in [6],[34]). Specifications of the diverse activities of Ter94/p97 and the fate of its substrates are mainly exerted by UBX domain protein co-factors, which eventually either promote or hinder p97's function in protein turnover; an example of the latter involves the dissociation of the SCF/Slimb/βTRCP E3 Ub ligase complex, eventually leading to its inactivation [45].…”

Ubiquitin- and ATP-dependent unfoldase activity of P97/VCP•NPLOC4•UFD1L is enhanced by a mutation that causes multisystem proteinopathy

“…In agreement with prior work, UN bridges the interaction of substrates with p97 (25,48). However, p97 also associates with other adaptor proteins, some of which (e.g., UBXN7) can cobind with UN and others (e.g., NSFL1C) of which bind in a mutually exclusive manner (36,37,46,90,91). Although there are examples of processes that require UN and an additional adaptor (42,92), in general, it is unclear whether the different adaptors work in different pathways, or work sequentially, together, or in opposition to one another in the same pathway.…”