Role of ubiquitination and proteolysis in the regulation of pro- and anti-apoptotic TNF-R1 signaling

•TNF-R1 signaling involves signaling from different cellular compartments.•Signaling from the plasma membrane results in cell survival.•Apoptosis signaling from TNF-R1 requires receptor internalization.•Proteolysis and ubiquitination are critically involved in both pathways.

Tumor Necrosis Factor Receptor 1 (TNF-R1) transmits various intracellular signaling cascades leading to diverse biological outcomes, ranging from proliferation, differentiation, survival to the induction of various forms of cell death (i.e. apoptosis, necrosis, necroptosis). These signaling pathways have to be tightly regulated. Proteolysis is an important regulatory mechanism in TNF-R1 pro-apoptotic as well as anti-apoptotic/pro-inflammatory signaling. Some key players in these signaling cascades are known (mainly the caspase-family of proteases and a previously unrecognized “lysosomal death pathway” involving cathepsins), however the interaction of proteases in the regulation of TNF signaling is still enigmatic. Ubiquitination of proteins, both non-degradative degradative, which either results in proteolytic degradation of target substrates or regulates their biological function, represents another layer of regulation in this signaling cascade.We and others found out that the differences in signal quality depend on the localization of the receptors. Plasma membrane resident receptors activate survival signals, while endocytosed receptors can induce cell death. In this article we will review the role of ubiquitination and proteolysis in these diverse events focusing on our own contributions to the lysosomal apoptotic pathway linked to the subcellular compartmentalization of TNF-R1. This article is part of a Special Issue entitled: Proteolysis as a Regulatory Event in Pathophysiology edited by Stefan Rose-John.