IFN-γ or IFN-α Ameliorates Chronic Proliferative Dermatitis by Inducing Expression of Linear Ubiquitin Chain Assembly Complex

Abstract

The linear ubiquitin chain assembly complex (LUBAC) ubiquitin ligase complex, composed of HOIL-1L–interacting protein (HOIP), heme-oxidized IRP2 ubiquitin ligase-1L (HOIL-1L), and SHANK-associated RH domain protein, specifically generates linear polyubiquitin chains and is involved in NF-κB activation. Lack of SHANK-associated RH domain protein, which drastically reduces the amount of HOIP and HOIL-1L, causes chronic proliferative dermatitis (cpdm) in mice. Impaired NF-κB activation and augmented apoptosis have been implicated in the pathogenesis of cpdm in mice. In this study, we found that IFN-γ increased the amount of LUBAC by inducing HOIP and HOIL-1L mRNA transcription and enhanced the signal-induced NF-κB activation in embryonic fibroblasts, keratinocytes, and bone marrow–derived macrophages from wild-type and/or cpdm mice; however, IFN-γ failed to augment NF-κB activation in mouse embryonic fibroblasts lacking linear polyubiquitination activity of LUBAC. Moreover, s.c. injection of IFN-γ for 3 wk into the skin of cpdm mice increased the amount of HOIP, suppressed apoptosis, and ameliorated the dermatitis. Inhibition of keratinocyte apoptosis by IFN-γ injection suppressed neutrophil, macrophage, and mast cell infiltration and the amount of TNF-α in the skin of cpdm mice. Similarly, IFN-α also enhanced the amount of HOIP as well as NF-κB activation, inhibited apoptosis, and ameliorated cpdm dermatitis. These results indicate that the IFNs enhance NF-κB activation and ameliorate cpdm dermatitis by augmenting expression of HOIP and HOIL-1L and linear polyubiquitination activity of LUBAC.

Roles of linear ubiquitinylation, a crucial regulator of NF‐κB and cell death, in the immune system

“…A recent report showed that the Rnf31 gene, which encodes HOIP, is located between the Psme2 and Irf9 genes, both of which are induced by interferon‐γ (IFN‐γ). In addition, the Rnf31 gene was shown to have an IFN regulatory factor 1 and two IFN‐γ‐responsive regulatory elements on the upstream and downstream regions of the genes respectively . As expected, mRNA transcription of HOIP was increased after IFN‐γ treatment.…”

“…As expected, mRNA transcription of HOIP was increased after IFN-c treatment. Increased protein levels of both HOIL-1L and SHARPIN in addition to HOIP were observed in MEFs, BMDMs, and primary keratinocytes in response to type I and type II IFN, which are induced mainly by immune cells including activated lymphocytes after RNA or DNA virus infection leading to enhanced activation of NF-jB (136). Moreover, intradermal injection of type I or type II IFN ameliorated cpdm dermatitis by upregulating HOIP expression in the skin, indicating that reduction of residual LUBAC underlies cpdm pathology.…”

Differential Involvement of the Npl4 Zinc Finger Domains of SHARPIN and HOIL-1L in Linear Ubiquitin Chain Assembly Complex-Mediated Cell Death Protection

“…Immunohistochemical analyses of the skin confirmed increased TNF-␣ production presumably from a number of infiltrated inflammatory cells in 5-week-old HOIL-1L ϩ/Ϫ SHARPIN cpdm/cpdm and 12-week-old SHARPIN cpdm/cpdm mice ( Fig. 3E) (31). Phosphorylation of the p65 subunit of NF-B is known to be a reliable marker of NF-B activation (32).…”

“…We previously observed that an interferon-mediated increase in LUBAC composed of HOIL-1L and HOIP ameliorates, but cannot completely cure, cpdm symptoms (31). Given that HOIP levels were lower in interferon-treated cpdm keratinocytes than in WT keratinocytes, augmented activation of antiapoptotic NF-B mediated by an increase in HOIL-1L/HOIP-containing LUBAC might not be able to completely override the augmented cell death caused by loss of SHARPIN.…”

Linear ubiquitin assembly complex regulates lung epithelial–driven responses during influenza infection

“…We next sought to identify the cytokine(s) necessary for the observed autocrine/paracrine regulation of HOIL-1L. It has been reported that IFN-α and IFN-γ can regulate the expression of LUBAC components in SHARPIN-deficient mice (43). In our mod-HOIL-1L has several LUBAC-independent functions, such as acting as an E3 ubiquitin ligase to target proteins such as PKCζ for degradation as seen in adaptation to hypoxia and cancer (23,31,39).…”