The ubiquitin ligase Cul5 regulates CD4+ T cell fate choice and allergic inflammation

Abstract

Antigen encounter directs CD4+ T cells to differentiate into T helper or regulatory cells. This process focuses the immune response on the invading pathogen and limits tissue damage. Mechanisms that govern T helper cell versus T regulatory cell fate remain poorly understood. Here, we show that the E3 ubiquitin ligase Cul5 determines fate selection in CD4+ T cells by regulating IL-4 receptor signaling. Mice lacking Cul5 in T cells develop Th2 and Th9 inflammation and show pathophysiological features of atopic asthma. Following T cell activation, Cul5 forms a complex with CIS and pJak1. Cul5 deletion reduces ubiquitination and subsequent degradation of pJak1, leading to an increase in pJak1 and pSTAT6 levels and reducing the threshold of IL-4 receptor signaling. As a consequence, Cul5 deficient CD4+ T cells deviate from Treg to Th9 differentiation in low IL-4 conditions. These data support the notion that Cul5 promotes a tolerogenic T cell fate choice and reduces susceptibility to allergic asthma.

The Cul5 E3 Ligase Complex Is a Key Negative Feedback Regulator of TCR/IL2 Signaling and Anti-Tumor Activity in CD8+T Cells

“…5a). Cish binds to Cul5 in CD4 T cells 41 and was upregulated upon TCR stimulation in CD8 + T cells, but not enriched in Cul5-HA IP sample either, suggesting a possible differential utilization of substrate receptors between CD4 + and CD8 + T cells.…”

“…mouse specific gene. Cul5 as a core element of E3 ligase complexes, on the other hand, has not been investigated in CD8 + T cells, despite a recent study reporting its regulation of CD4 + T helper cell differentiation 41 . Therefore, we decided to investigate Cul5 further.…”

“…Among top enriched gene (Pik3ap1, Cul5 and Zf865) KO in the effector cluster, the role of Pik3ap1 in CD8 + T cell activation through PI3K signaling has been reported 64 , while Zf865 is a mouse specific gene. Cul5 as a core element of E3 ligase complexes, on the other hand, has not been investigated in CD8 + T cells, despite a recent study reporting its regulation of CD4 + T helper cell differentiation 41 . Therefore, we decided to investigate Cul5 further.…”

“…The CIS/SOCS family SOCS-box-containing proteins bind to Cul5 with variable affinities through the SOCS-box domain 38 , and some of these proteins including Cish, SOCS1 and SOCS3 have been shown to play regulatory roles in T cell activation by targeting cytokine and TCR signaling 39, 40 . However, it is not known whether the Cul5 E3 ligase complexes regulate CD8 + T cell activation or function through any of these CIS/SOCS family proteins in CD8 + T cells despite Cul5 regulates pJak1 degradation by interacting with Cish in CD4 cells 41 . Neddylation is a critical modification of CRLs to induce their conformational changes and subsequent activation 42 .…”

How GRAIL controls Treg function to maintain self-tolerance

“…In T regs from healthy controls, GRAIL acts as a competitive inhibitor of neddylation by ubiquitinating the exact lysine on cullin5 that needs to be neddylated to activate the CRL. Thus, in Tregs, GRAIL acts as a competitive inhibitor of neddylation and blocks activation of the cullin5 CRLs that normally degrade pJAK1 and Deptor in IL-2 activated CD4 T effector cells (11)(12)(13). GRAIL protein but not GRAIL mRNA expression is reduced in T regs from SLE patients.…”