Analysis of human tumour necrosis factor receptor 1 dominant-negative mutants reveals a major region controlling cell surface expression

Tumour necrosis factor receptor 1 (TNFR1) plays a critical role in host defence and inflammation. We have identified a membrane proximal region (aa 218-324) of TNFR1 that restricts surface expression. This was prompted by comparing the dominant-negative properties of a C-terminal truncation of TNFR1 with a point mutant that prevents signalling. C-terminal truncation (aa 218-426) generates a better dominant-negative TNFR1 mutant than inactivation of the death domain by point mutation. The increased dominant-negative activity correlates with increased cell surface expression. The membrane proximal region is the most important region of the receptor for restricting expression.