sec mutants accelerate turnover of CFTR and δF508 CFTR-role for stress responses

Academic Article

Abstract

  • Conformationally abnormal secretory and membrane proteins characterstic of a number of diseases do not pass from the ER downstream along the secretoy path. It is not known what consequences, if any, this has for the continued functioning of the cell. To explore this issue, we have expressed wild type and mutant forms of an ABC transporter membrane protein, the human cystic fibrosis transmembrane regulator (CFTR) in yeast. As in animal cells, most CFTR (and the most common mutant form, δF508 CFTR) is restricted to the ER when expressed in yeast. Strikingly the degradation of CFTR and the mutant protein are accelerated in both early- and late-acting sec mutants. (sec18-1, sec7-1 and sec1-1), while the turnover of Kar2p (an ER resident protein) is unaffected. Acceleration of the mutant protein turnover is also seen in a ts ssa1 ssa2 double disruption mutant, which overexpresses several heat shock proteins. We find that expression of either CFTR or the mutant form of CFTR induces a strong and persistent stress response, showing that mutant proteins signal their presence. This stress response may be due to stable interaction of CFTR and the mutant protein with Ssa proteins, as is observed for δF508CFTR, which is destined to be degraded in animal cells. Acceleration of protein turnover observed in sec strains may be an adaptive response in face of the interruption of membrane transport.
  • Published In

  • The FASEB Journal  Journal
  • Author List

  • Nanduri J; Liang L; Bedwell DM; Tartakoff AM
  • Volume

  • 12
  • Issue

  • 5