Ube2j2 ubiquitinates hydroxylated amino acids on ER-associated degradation substrates.
Ubiquitin (Ub) modification of proteins plays a prominent role in the regulation of multiple cell processes, including endoplasmic reticulum-associated degradation (ERAD). Until recently, ubiquitination of substrates was thought to occur only via isopeptide bonds, typically to lysine residues. Several recent studies suggest that Ub can also be coupled to nonlysine residues by ester/thiolester bonds; however, the molecular basis for these novel modifications remains elusive. To probe the mechanism and importance of nonlysine ubiquitination, we have studied the viral ligase murine K3 (mK3), which facilitates the polyubiquitination of hydroxylated amino acids serine/threonine on its ERAD substrate. In this paper, we identify Ube2j2 as the primary cellular E2 recruited by the mK3 ligase, and this E2-E3 pair is capable of conjugating Ub on lysine or serine residues of substrates. However, surprisingly, Ube2j2-mK3 preferentially promotes ubiquitination of hydroxylated amino acids via ester bonds even when lysine residues are present on wild-type substrates, thus establishing physiological relevance of this novel ubiquitination strategy.
Wang
Xiaoli
X
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.
Herr
Roger A
RA
Rabelink
Martijn
M
Hoeben
Rob C
RC
Wiertz
Emmanuel J H J
EJ
Hansen
Ted H
TH
D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D033862:Iron-Binding Proteins / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D008025:Ligases / Q000737:chemistry / Q000235:genetics / Q000502:physiology; D008285:Major Histocompatibility Complex; D051379:Mice; D008969:Molecular Sequence Data; D017434:Protein Structure, Tertiary; D016415:Sequence Alignment; D044763:Ubiquitin-Conjugating Enzymes / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D054875:Ubiquitination
D033862:Iron-Binding Proteins; C546318:UBE2J2 protein, mouse; C490789:Ube2d1 protein, mouse; D044763:Ubiquitin-Conjugating Enzymes; D008025:Ligases