title: The N-end rule proteolytic system in autophagy.
abstract: The N-end rule pathway is a cellular proteolytic system that utilizes specific N-terminal residues as degradation determinants, called N-degrons. N-degrons are recognized and bound by specific recognition components (N-recognins) that mediate polyubiquitination of low-abundance regulators and selective proteolysis through the proteasome. Our earlier work identified UBR4/p600 as one of the N-recognins that promotes N-degron-dependent proteasomal degradation. In this study, we show that UBR4 is associated with cellular cargoes destined to autophagic vacuoles and is degraded by the lysosome. UBR4 loss causes multiple misregulations in autophagic pathways, including an increased formation of LC3 puncta. UBR4-deficient mice die during embryogenesis primarily due to defective vascular development in the yolk sac (YS), wherein UBR4 is associated with a bulk lysosomal degradation system that absorbs maternal proteins from the YS cavity and digests them into amino acids. Our results suggest that UBR4 plays a role not only in selective proteolysis of short-lived regulators through the proteasome, but also bulk degradation through the lysosome. Here, we discuss a possible mechanism of UBR4 as a regulatory component in the delivery of cargoes destined to interact with the autophagic core machinery.
authors.affiliation: Center for Pharmacogenetics and Department of Pharmaceutical Sciences; School of Pharmacy; University of Pittsburgh; Pittsburgh, PA USA.
authors.forename: Sung Tae
authors.initials: ST
authors.lastname: Kim
authors.forename: Takafumi
authors.initials: T
authors.lastname: Tasaki
authors.forename: Adriana
authors.initials: A
authors.lastname: Zakrzewska
authors.forename: Young Dong
authors.initials: YD
authors.lastname: Yoo
authors.forename: Ki
authors.initials: K
authors.lastname: Sa Sung
authors.forename: Su-Hyeon
authors.initials: SH
authors.lastname: Kim
authors.forename: Hyunjoo
authors.initials: H
authors.lastname: Cha-Molstad
authors.forename: Joonsung
authors.initials: J
authors.lastname: Hwang
authors.forename: Kyoung A
authors.initials: KA
authors.lastname: Kim
authors.forename: Bo Yeon
authors.initials: BY
authors.lastname: Kim
authors.forename: Yong Tae
authors.initials: YT
authors.lastname: Kwon
mesh_terms: D000818:Animals; D001343:Autophagy; D002148:Calmodulin-Binding Proteins / Q000378:metabolism; D004622:Embryo, Mammalian / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008954:Models, Biological; D059748:Proteolysis
chemical_list: D002148:Calmodulin-Binding Proteins
keywords: N-recognin; UBR box; UBR4; angiogenesis; ubiquitin ligase; yolk sac