ASB17 Facilitates the Burst of LPS-Induced Inflammation Through Maintaining TRAF6 Stability.

Pin Wan,Ge Yang,Xu Che,Xulin Chen,Wen Zhang,Yongkui Li,Simeng Zhang,Yaling Jia,Jianguo Wu,Pan Pan,Geng Li,Qiuping Tan,Qiwei Zhang,Zhen Luo,Yaru Zhang

doi:10.3389/fcimb.2022.759077

Abstract

ASB17, a member of the ankyrin repeat and SOCS box-containing protein (ASB) family, has been supposed to act as an E3 ubiquitin ligase. Actually, little is known about its biological function. In this study, we found that ASB17 knocking-out impaired the expression of the pro-inflammatory cytokines CCL2 and IL-6 in bone marrow-derived dendritic cells (BMDCs) stimulated by lipopolysaccharide (LPS), indicating an inflammation-promoting role of this gene. We reveal that ASB17 promotes LPS-induced nuclear factor kappa B (NF-κB) signal activation through interacting with TNF receptor-associated factor 6 (TRAF6) which is a crucial adaptor protein downstream of toll-like receptors (TLR). ASB17 via its aa177–250 segment interacts with the Zn finger domain of TRAF6. The interaction of ASB17 stabilizes TRAF6 protein through inhibiting K48-linked TRAF6 polyubiquitination. Therefore, we suggest that ASB17 facilitates LPS-induced NF-κB activation by maintaining TRAF6 protein stability. The inflammation enhancer role of ASB17 is recognized here, which provides new understanding of the activation process of inflammation and immune response.

Highlights

The ankyrin repeat and suppressor of cytokine signaling (SOCS) box-containing protein (ASB) family containing 18 members has been identified as an E3 ubiquitin ligase family (Kohroki et al, 2005; Liu et al, 2019)
We found that ASB17 interacted with TNF receptor-associated factor 6 (TRAF6) and suppressed K48-linked polyubiquitination of TRAF6, by which it stabilizes the TRAF6 protein
It is reported that ASB17 is mainly expressed in the testis, and we have found that ASB17 promotes testis cell apoptosis through degrading BCLW and MCL1 (Yang et al, 2021)

Summary

INTRODUCTION

The ankyrin repeat and suppressor of cytokine signaling (SOCS) box-containing protein (ASB) family containing 18 members has been identified as an E3 ubiquitin ligase family (Kohroki et al, 2005; Liu et al, 2019). ASB17 Facilitates TRAF6-Mediated Inflammation biological function in inflammatory signaling was investigated in this work. The TRAF6-mediated NF-kB signal pathway is involved in multiple pathological processes and especially essential for inflammatory diseases, which makes TRAF6 become a key modulating target of inflammation (Dainichi et al, 2019). BICP0 and TRIM38 negatively regulate TRAF6-mediated NF-kB by promoting the K48-linked ubiquitination and degradation of TRAF6 (Zhao et al, 2012; Cao et al, 2019). ASB17 facilitates the induction of pro-inflammatory cytokines via suppressing TRAF6 K48-linked ubiquitination. These will provide more knowledge about the TRAF6-mediated NF-kB signal pathway

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RESULTS

DISCUSSION

ETHICS STATEMENT