Fig. 9

Model of the molecular events comprising an autophagy-mediated, inhibitory cross-talk with the TGFβ pathway in RAS-transformed cells. Selective autophagy of TRAF3 via cargo receptors, such as NDP52, terminates the tonic inhibition of the alternative NF-κB pathway that is ordinarily observed in unstimulated primary cells. This results in nuclear activity of RELB. Downstream of TGFβ, frequently present in the tumour milieu, DNA binding by SMADs drives gene transcription. Directly TGFβ-responsive gene promoters recruit SMAD complexes to SMAD-response elements (SREs). However, RELB has the ability to repress SRE-containing gene promoters. This occurs not via interaction with NF-κB consensus sites but instead via recruitment to chromatin by protein–protein interaction with active SMAD complexes. Thus, transcriptionally repressive RELB effectively ‘hijacks’ SMAD promoters to exert negative feedback on TGFβ-mediated transcription. In the absence of autophagy, the above events involving RELB are not engaged. Thus, in vivo, autocrine and/or paracrine sources of TGFβ repress tumorigenesis when autophagy is ablated. Please note though, that in in vivo models other than A549 cells, it is possible that altered sensitivity to TGFβ could potentially have other phenotypic outcomes