Degradation of human thyroperoxidase in the endoplasmic reticulum involvestwo different pathways depending on the folding state of the protein

Human thyroperoxidase (hTPO), a type I transmembrane glycoprotein, plays a key role in thyroid hormone synthesis. In a previous paper (Fayadat, L., Ni ccoli, P., Lanet, J., and Franc, J. L. (1998) Endocrinology 139, 4277-4285) we established that after the synthesis, only 15-20% of the hTPO molecules were recognized by a monoclonal antibody (mAb15) directed against a confor mational structure and that only 2% were able to reach the cell surface. In the present study using pulse-chase experiments in the presence or absence of protease inhibitors followed by immunoprecipitation procedures with mon oclonal antibodies recognizing unfolded or partially folded hTPO forms we s how that: (i) unfolded hTPO forms are degraded by the proteasome and (ii) p artially folded hTPO forms are degraded by other proteases. It was also est ablished upon incubating endoplasmic reticulum (ER) membranes in vitro that the degradation of the partially folded hTPO was carried out by serine and cysteine integral ER membrane proteases, These data provide valuable insig hts into the quality control mechanisms whereby the cells get rid of misfol ded or unfolded proteins. Moreover, this is the first study describing a pr otein degradation process involving two distinct degradation pathways (prot easome and ER cysteine/serine proteases) at the ER level, depending on the folding state of the protein.