Ziegler 2018 Cell

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Ziegler PK, Bollrath J, Pallangyo CK, Matsutani T, Canli Ö, De Oliveira T, Diamanti MA, Müller N, Gamrekelashvili J, Putoczki T, Horst D, Mankan AK, Öner MG, Müller S, Müller-Höcker J, Kirchner T, Slotta-Huspenina J, Taketo MM, Reinheckel T, Dröse S, Larner AC, Wels WS, Ernst M, Greten TF, Arkan MC, Korn T, Wirth D, Greten FR (2018) Mitophagy in intestinal epithelial cells triggers adaptive immunity during tumorigenesis. Cell 174:88-101.

» PMID: 29909986

Ziegler PK, Bollrath J, Pallangyo CK, Matsutani T, Canli Oe, De Oliveira T, Diamanti MA, Mueller N, Gamrekelashvili J, Putoczki T, Horst D, Mankan AK, Oener MG, Mueller S, Mueller-Hoecker J, Kirchner T, Slotta-Huspenina J, Taketo MM, Reinheckel T, Droese S, Larner AC, Wels WS, Ernst M, Greten TF, Arkan MC, Korn T, Wirth D, Greten FR (2018) Cell

Abstract: In colorectal cancer patients, a high density of cytotoxic CD8+ T cells in tumors is associated with better prognosis. Using a Stat3 loss-of-function approach in two wnt/β-catenin-dependent autochthonous models of sporadic intestinal tumorigenesis, we unravel a complex intracellular process in intestinal epithelial cells (IECs) that controls the induction of a CD8+ T cell based adaptive immune response. Elevated mitophagy in IECs causes iron(II)-accumulation in epithelial lysosomes, in turn, triggering lysosomal membrane permeabilization. Subsequent release of proteases into the cytoplasm augments MHC class I presentation and activation of CD8+ T cells via cross-dressing of dendritic cells. Thus, our findings highlight a so-far-unrecognized link between mitochondrial function, lysosomal integrity, and MHC class I presentation in IECs and suggest that therapies triggering mitophagy or inducing LMP in IECs may prove successful in shifting the balance toward anti-tumor immunity in colorectal cancer.

Keywords: Stat3, Adaptive immunity, Antigen processing, Colon cancer, Cross dressing, Intestinal epithelial cells, Lysosomal membrane permeabilization, Mitophagy Bioblast editor: Kandolf G O2k-Network Lab: DE Frankfurt Droese S


Labels: MiParea: Respiration  Pathology: Cancer 

Organism: Mouse  Tissue;cell: Endothelial;epithelial;mesothelial cell  Preparation: Intact cells 


Coupling state: LEAK, ET 

HRR: Oxygraph-2k 

Labels, 2018-07