TRIM31 facilitates K27-linked polyubiquitination of SYK to regulate antifungal immunity

Xueer Wang,Tian Chen,Zhugui Shao,Yi Zheng,Lingli Kong,Xiaorong Chen,Chao Sui,Xinming Jia,Wanxin Zhuang,Chengjiang Gao,Bingyu Liu,Jinxiu Hou,Honghai Zhang,Hansen Liu,Lei Zhang,Feng Liu

doi:10.1038/s41392-021-00711-3

Abstract

Spleen tyrosine kinase (SYK) is a non-receptor tyrosine kinase, which plays an essential role in both innate and adaptive immunity. However, the key molecular mechanisms that regulate SYK activity are poorly understood. Here we identified the E3 ligase TRIM31 as a crucial regulator of SYK activation. We found that TRIM31 interacted with SYK and catalyzed K27-linked polyubiquitination at Lys375 and Lys517 of SYK. This K27-linked polyubiquitination of SYK promoted its plasma membrane translocation and binding with the C-type lectin receptors (CLRs), and also prevented the interaction with the phosphatase SHP-1. Therefore, deficiency of Trim31 in bone marrow-derived dendritic cells (BMDCs) and macrophages (BMDMs) dampened SYK-mediated signaling and inhibited the secretion of proinflammatory cytokines and chemokines against the fungal pathogen Candida albicans infection. Trim31−/− mice were also more sensitive to C. albicans systemic infection than Trim31+/+ mice and exhibited reduced Th1 and Th17 responses. Overall, our study uncovered the pivotal role of TRIM31-mediated K27-linked polyubiquitination on SYK activation and highlighted the significance of TRIM31 in anti-C. albicans immunity.

Highlights

Fungal infections are major public health threats, especially HIV patients,[1] immune-compromised people with hematopoietic stem cell transplantation (HSCT) and chemotherapy,[2] or primary immune deficiencies.[3]
We found TRIM31 substantially increased study first reported that Spleen tyrosine kinase (SYK) was modified through K27-linked SYK polyubiquitination in the presence of K27, but not with other polyubiquitination by TRIM31 upon fungal infection, and ubiquitin mutants (Fig. 1d), indicating TRIM31 mainly promotes uncovered its significance in positively regulating the activation K27-linked polyubiquitination of SYK
C. albicans is the major inducer of anti-fungal immunoglobulin G (IgG),[50] we found that Trim31−/− mice showed significantly reduced production of IgG in their serum after 5 days infection as compared with Trim31+/+ mice

Summary

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Fungal infections are major public health threats, especially HIV patients,[1] immune-compromised people with hematopoietic stem cell transplantation (HSCT) and chemotherapy,[2] or primary immune deficiencies.[3]. TRIM31 did not ubiquitinate the CLRs including responses, possibly due to the encoding genes locating in the Dectin-1, Dectin-2, Dectin-3, Mincle, and the adaptor FcR-γ locus which encoding the major histocompatibility complex (Supplementary Fig. S1d) Overall, these results indicate that (MHC) class I proteins.[38] Our laboratory has previously reported TRIM31 catalyzes the polyubiquitination of SYK. We found TRIM31 substantially increased study first reported that SYK was modified through K27-linked SYK polyubiquitination in the presence of K27, but not with other polyubiquitination by TRIM31 upon fungal infection, and ubiquitin mutants (Fig. 1d), indicating TRIM31 mainly promotes uncovered its significance in positively regulating the activation K27-linked polyubiquitination of SYK.

RESULTS

DISCUSSION

Findings

MATERIALS AND METHODS