RING-between-RINGs-keeping the safety on loaded guns
Authors: Dove, Katja K.; Klevit, Rachel E.
The 'RING-between-RING'-type E3 ubiquitin ligase HOIP acts via a novel RING/HECT-hybrid ubiquitin transfer mechanism and catalyses the formation of linear ubiquitin chains by non-covalently binding the acceptor ubiquitin. But in the absence of a binding partner, HOIP is auto-inhibited. This explains why assembly of either HOIP/HOIL-1L or HOIP/SHARPIN is required to catalyse linear chain formation.
The HOIL-1L ligase modulates immune signalling and cell death via monoubiquitination of LUBAC
NATURE CELL BIOLOGY
Authors: Fuseya, Yasuhiro; Fujita, Hiroaki; Kim, Minsoo; Ohtake, Fumiaki; Nishide, Akira; Sasaki, Katsuhiro; Saeki, Yasushi; Tanaka, Keiji; Takahashi, Ryosuke; Iwai, Kazuhiro
Fuseya et al. show that HOIL-1L catalyses monoubiquitination on all three LUBAC subunits, thereby impairing the function of LUBAC and its role in infection defence and dermatitis pathogenesis. The linear ubiquitin chain assembly complex (LUBAC), which consists of HOIP, SHARPIN and HOIL-1L, promotes NF-kappa B activation and protects against cell death by generating linear ubiquitin chains. LUBAC contains two RING-IBR-RING (RBR) ubiquitin ligases (E3), and the HOIP RBR is responsible for catalysing linear ubiquitination. We found that HOIL-1L RBR plays a crucial role in regulating LUBAC. HOIL-1L RBR conjugates monoubiquitin onto all LUBAC subunits, followed by HOIP-mediated conjugation of linear chains onto monoubiquitin, and these linear chains attenuate the functions of LUBAC. The introduction of E3-defective HOIL-1L mutants into cells augmented linear ubiquitination, which protected the cells against Salmonella infection and cured dermatitis caused by reduced LUBAC levels due to SHARPIN loss. Our results reveal a regulatory mode of E3 ligases in which the accessory E3 in LUBAC downregulates the main E3 by providing preferred substrates for autolinear ubiquitination. Thus, inhibition of HOIL-1L E3 represents a promising strategy for treating severe infections or immunodeficiency.