| First Author | Shimizu S | Year | 2016 |
| Journal | Mol Cell Biol | Volume | 36 |
| Issue | 10 | Pages | 1569-83 |
| PubMed ID | 26976635 | Mgi Jnum | J:236193 |
| Mgi Id | MGI:5805343 | Doi | 10.1128/MCB.01049-15 |
| Citation | Shimizu S, et al. (2016) Differential Involvement of the Npl4 Zinc Finger Domains of SHARPIN and HOIL-1L in Linear Ubiquitin Chain Assembly Complex-Mediated Cell Death Protection. Mol Cell Biol 36(10):1569-83 |
| abstractText | The linear ubiquitin chain assembly complex (LUBAC) participates in NF-kappaB 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. |
