Abnormal protein translocation as the elusive cause of cystic fibrosis: an hypothesis

Abstract

Despite the recent rapid advances in isolation of the abnormal gene responsible for cystic fibrosis, there remains the need to explain the mechanism by which a single gene mutation causes the widespread clinical effects seen in this disease. Careful review of the otherwise unexplained abnormalities of cystic fibrosis from the perspective of cell biology reveals the following common features: (1) all these abnormalities involve proteins which are either (A) inserted into cell membranes in the RER and arrested after partial translocation or (B) inserted into RER membranes and fully translocated to be compartmentalized away from the cytosol in secretory vacuoles, lysosomes or peroxisomes; (2) all the involved proteins have minor abnormalities in their physicochemical properties or activity functions; (3) none of the involved proteins are missing or totally deficient in function; (4) final compartmentalization of the involved proteins is unaffected. These observations have directed our attention to the process by which most proteins are inserted into and translocated across lipid bilayer membranes, namely the signal peptide mechanism. This mechanism, not previously examined in cystic fibrosis, is reviewed in detail. Of the major proteins controlling signal peptide translocation, deficiencies in the function of signal peptidase activity appear most capable of causing the effects seen in cystic fibrosis.