Prof. Di Wu
Institute of Translational Medicine, Zhejiang University School of Medicine, China
Title: Neddylation-CRLs in Treg cells: pivotal function and complex regulation
Abstract:
Neddylation-mediated
activation of Cullin-RING E3 Ligases (CRLs) are necessary for the degradation
of specific immune regulatory proteins. However, little is known about how
these processes govern the function of regulatory T (Treg) cells. We show that
mice with Treg cell-specific deletion of Rbx1, a dual E3 for both neddylation
and ubiquitylation by CRLs, develop an early-onset fatal inflammatory disorder,
characterized by disrupted Treg cell homeostasis and suppressive functions.
Specifically, Rbx1 is essential for the maintenance of an effector Treg cell
subpopulation, and regulates several inflammatory pathways. Similar but less
severe phenotypes are observed in mice having Ube2m, a neddylation E2
conjugation enzyme, deleted in their Treg cells. Thus, above work demonstrates
that the Ube2m-Rbx1 axis is specifically required for intrinsic regulatory
processes in Treg cells; and that Rbx1 might also play Ube2m-independent roles
in maintaining the fitness of Treg cells.
Interestingly,
Treg-specific deletion of Rbx2/Sag or Ube2f, components of a similar but
distinct neddylation-CRL complex, yields no obvious phenotype. Whether these
E2s or E3s compensate each other in functional regulations of Treg cells is,
however, previously unknown. We further generated Foxp3Cre;Ube2mfl/fl;Ube2ffl/fl or Foxp3Cre;Rbx1fl/fl;Sagfl/fl double-null mice by simultaneous deletion of both neddylation E2s or E3s in Treg
cells, respectively. Remarkably, Ube2m&Ube2f double-null mice
developed much severe autoimmune phenotypes than did Ube2m-null mice,
indicating that Ube2m markedly compensates Ube2f in Treg cells.
The minor worsened autoimmune phenotypes seen at the very early stage in Rbx1&Sag double-null than Rbx1-null mice is likely due to already severe
phenotypes of the later, indicating a minor compensation of Rbx1 for Sag.
The RNA profiling-based analyses revealed that up- and down-regulations of few
signaling pathways in Treg cells are associated with the severity of autoimmune
phenotypes. Finally, severer inflammation phenotypes seen in mice with double
E3-null than with double E2-null Treg cells indicate a neddylation-independent
mechanism of 2 E3s, also known to serve as the RING component of CRLs in regulation
of Treg cell fitness.
Biography:
2017-present Research Assistant Professor
Institute of Translational Medicine, Zhejiang University School of Medicine, China
● 2014-2017 Postdoctoral fellow
Institute of Hematology, Peking Union Medical College, China
● 2010-2013 Doctor of philosophy
College of Life Sciences, Nankai University, China
● 2007-2010 Master
College of Life Sciences, Nankai University, China
● 2003-2007 Bachelor
College of Life Sciences, Nankai University, China