Linear Ubiquitin Chain Assembly Complex (LUBAC) (LUBAC)

The Linear Ubiquitin Chain Assembly Complex (LUBAC) is a multi-subunit E3 ubiquitin ligase composed of HOIP (RNF31), HOIL-1L (RBCK1), and SHARPIN [1]. It is uniquely characterized by its ability to catalyze the formation of M1-linked (linear) ubiquitin chains, which are critical regulators of the canonical NF-kappaB signaling pathway [2]. By attaching linear ubiquitin chains to substrates such as NEMO (IKK-gamma), LUBAC facilitates the recruitment and activation of the IKK complex, leading to the transcription of genes involved in inflammation, immune response, and cell survival [3]. Dysregulation of LUBAC is implicated in several pathologies, including activated B-cell-like diffuse large B-cell lymphoma (ABC-DLBCL), where it promotes oncogenic signaling, and various autoinflammatory and immunodeficiency syndromes [4, 5]. Because of its central role in pro-survival signaling, LUBAC is an attractive therapeutic target for cancer and chronic inflammatory diseases [6]. Small-molecule inhibitors, such as HOIPINs, are currently being developed to selectively block the catalytic activity of the HOIP subunit to dampen pathological NF-kappaB activation [7]. Sources: [1] Kirisako et al. (2006) EMBO J; [2] Tokunaga et al. (2009) Nature; [3] Gerlach et al. (2011) Nature; [4] Yang et al. (2014) Cancer Cell; [5] Boisson et al. (2012) J Exp Med; [6] Kloetgen et al. (2020) Commun Biol; [7] Katsuya et al. (2018) Biochem J.

Other names

HOIP-HOIL-1L-SHARPIN complexM1-linked ubiquitin ligase complexRNF31-RBCK1-SHARPIN complexLinear ubiquitin signaling pathway

Inhibition of the HOIP subunit's catalytic RBR domain to prevent the assembly of M1-linked ubiquitin chains, thereby blocking the activation of the IKK complex and downstream NF-kappaB signaling.