title: Differential Involvement of the Npl4 Zinc Finger Domains of SHARPIN and HOIL-1L in Linear Ubiquitin Chain Assembly Complex-Mediated Cell Death Protection.
abstract: The linear ubiquitin chain assembly complex (LUBAC) participates in NF-κB activation and cell death protection. Loss of any of the three LUBAC subunits (catalytic HOIP, accessory HOIL-1L, or accessory SHARPIN subunit) leads to distinct phenotypes in mice and human. cpdm mice (chronic proliferative dermatitis in mice [cpdm]) that lack SHARPIN exhibit chronic inflammatory phenotypes, whereas HOIL-1L knockout mice exhibit no overt phenotypes, despite sharing highly homologous ubiquitin-like (UBL) and Npl4 zinc finger (NZF) domains. Here, we intercrossed mice lacking HOIL-1L and SHARPIN and found that reduction of HOIL-1L in cpdm mice exacerbated inflammatory phenotypes without affecting characteristic features of cpdm disease, whereas reduction of SHARPIN in HOIL-1L knockout mice provoked no overt phenotypes. Hence, loss of SHARPIN and reduction of LUBAC triggers cpdm phenotypes. We found that the NZF domain of SHARPIN, but not that of HOIL-1L, is critical for effective protection from programmed cell death by enhancing the recruitment of LUBAC to the activated TNFR complex. The binding activity to K63-linked ubiquitin chains that the NZF domain of SHARPIN, but not that of HOIL-1L, possesses appears to be involved in the recruitment. Thus, selective recognition of ubiquitin chains by NZFs in LUBAC underlies the regulation of LUBAC function.
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan Department of Anesthesia, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Shimizu
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Fujita
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Yoshiteru
authors.initials: Y
authors.lastname: Sasaki
authors.affiliation: Department of Diagnostic Pathology, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Tatsuaki
authors.initials: T
authors.lastname: Tsuruyama
authors.affiliation: Department of Anesthesia, Kyoto University Hospital, Kyoto, Japan.
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: Department of Molecular and Cellular Physiology, Graduate School of Medicine, Kyoto University, Kyoto, Japan kiwai@mcp.med.kyoto-u.ac.jp.
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Iwai
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000737:chemistry* / Q000235:genetics*; D016923:Cell Death; D003433:Crosses, Genetic; D055786:Gene Knockout Techniques; D005804:Genes, Lethal; D047908:Intracellular Signaling Peptides and Proteins; D008239:Lysine / Q000378:metabolism; D051379:Mice; D055503:Protein Multimerization; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism; D014452:Ubiquitins / Q000737:chemistry / Q000378:metabolism*; D016335:Zinc Fingers; D044767:Ubiquitin-Protein Ligases
chemical_list: D002352:Carrier Proteins; D047908:Intracellular Signaling Peptides and Proteins; D008239:Lysine; D018124:Receptors, Tumor Necrosis Factor; D014452:Ubiquitins; C554944:Sipl1 protein, mouse; C000607389:Rbck1 protein, mouse; D044767:Ubiquitin-Protein Ligases