Neddylation‐CRLs regulate the functions of Treg immune cells

Abstract

Neddylation, a ubiquitylation-like post-translational modification, is catalyzed by a cascade composed of three enzymes: E1 activating enzyme, E2 conjugating enzyme, and E3 ligase with cullins as physiological substrates. Specifically, neddylation E2 UBE2M couples with E3 RBX1 to neddylate cullins 1-4, whereas neddylation E2 UBE2F couples with E3 RBX2/SAG to neddylate cullin 5, leading to activation of CRL1-4 (Cullin-RING ligases 1-4) and CRL5, respectively. While over-activation of the neddylation-CRLs axis occurs frequently in many human cancers, how neddylation-CRLs regulate the function of immune cells, particularly Treg cells was previously unknown. To this end, we recently performed Treg selective knockout of two neddylation E2s and two E3s, individually, driven by Foxp3-Cre, and found that while the Ube2f-Sag E2/E3 pair plays a minimal role, if any, the Ube2m-Rbx1 pair is essential for the maintenance of Treg functionality, since their deletion triggers robust inflammatory response with autoimmune phenotypes. Milder phenotype severity upon Treg KO of upstream Ube2m than that of downstream Rbx1 strongly suggested that Rbx1 regulates Treg function in a manner dependent and independent of neddylation.

Single-cell sequencing analysis and multiple machine-learning models revealed the cellular crosstalk of dendritic cells and identified FABP5 and KLRB1 as novel biomarkers for psoriasis

“…FABP5 has been widely reported in autoimmune diseases such as multiple sclerosis, inflammatory neuronal remodeling, and DCs dysregulation ( 25 – 27 ). Similarly, CD47 and UBE2F are involved in aberrant functions of DCs and T cells in various tumors ( 28 – 30 ), indicating their potential relevance to psoriasis development. The random forest algorithm thus demonstrated high accuracy in predicting psoriasis.…”

The Double-Edged Effects of MLN4924: Rethinking Anti-Cancer Drugs Targeting the Neddylation Pathway

“…For tumor-infiltrating lymphocytes (TILs), MLN4924 could target CD8+ T cells and enhance their cytotoxicity by promoting TNF-α and IFN-γ expression [17]. In addition to promoting the anti-cancer immunity mediated by cytotoxic T cells, MLN4924 can also inhibit immunosuppression involving regulatory T cells (Tregs) by abrogating their expansion and differentiation [52,67]. For non-immune cells within the TME, MLN4924 can deprive cancer cells of their metastatic capacity by restricting the neddylation-mediated pro-cancer functions of stromal cells such as CAFs and VECs [18,19].…”