Selective degradation of PU.1 during autophagy represses the differentiation and antitumour activity of T9 cells
Authors: Isis Benoit-Lizon
Tiffany Martin
Fran√ßois Ghiringhelli
Zhijian Cai
Aur√©lie Roussey
Richard A Flavell
Magalie Dosset
Thaiz Rivera Vargas
Lionel Apetoh
Yingying Shen
Journal: Nature Communications (2017)
Discipline: Multidisciplinary
Keywords: Autophagy; T helper 9 cells; Differentiation; IL-9; PU.1
Affiliations: INSERM, U1231, Dijon, 21000, France., Universit√© de Bourgogne Franche Comt√©, Dijon, 21000, France., Institute of Immunology, Zhejiang University School of Medicine, Hangzhou, People's Republic of China., Etablissement Fran√ßais du Sang, Besan√ßon, 25000, France., Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, 06520, USA., Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, 06520, USA., INSERM, U1231, Dijon, 21000, France. ., Universit√© de Bourgogne Franche Comt√©, Dijon, 21000, France. ., Centre Georges Fran√ßois Leclerc, Dijon, 21000, France. .

Abstract:  Autophagy, a catabolic mechanism that involves degradation of cellular components, is essential for cell homeostasis. Although autophagy favours the lineage stability of regulatory T cells, the contribution of autophagy to the differentiation of effector CD4 T cells remains unclear. Here we show that autophagy selectively represses T helper 9 (TH9) cell differentiation. CD4 T cells lacking Atg3 or Atg5 have increased interleukin-9 (IL-9) expression upon differentiation into TH9 cells relative to Atg3- or Atg5-expressing control cells. In addition, the TH9 cell transcription factor, PU.1, undergoes K63 ubiquitination and degradation through p62-dependent selective autophagy. Finally, the blockade of autophagy enhances TH9 cell anticancer functions in vivo, and mice with T cell-specific deletion of Atg5 have reduced tumour outgrowth in an IL-9-dependent manner. Overall, our findings reveal an unexpected function of autophagy in the modulation of TH9 cell differentiation and antitumour activity, and prompt potential autophagy-dependent modulations of TH9 activity for cancer immunotherapy.Autophagy is a cellular process for recycling cell constituents, and is essential for T cell activation, but its function in T cell polarization is still unclear. Here the authors show that autophagy induces the degradation of transcription factor PU.1 to negatively modulate TH9 homeostasis and antitumour immunity. 

Retracted: No

PubPeer comments:
 Figure 2D, 4G and 5M: Loading controls seem to come from a different gel or different samples, they don t fit the displayed lanes. , 
 Figure 4f. PU.1 and beta-Actin (very similar molecular weights) panels do not look like they come from the same blot (especially lanes 2 and 4). https: imgur.com GyiBD7s , 
 some of the full western blot in the supplementary document are different from western blot shown in the main figures , 
 In this paper, the western blot pictures in the supplementary document (full or uncropped western blot) are for many blot very different to the ones shown in the main figures. In the pictures below are the discrepancies found;    ,