Figure 12

Proposed model of the mechanisms mediating degradation of the hIP. (A), synthesis of the hIP begins in the rough ER. The hIP is then subject to co-and post-translational modifications, such as N-linked glycosylation and disulphide bond formation which, along with interaction with essential molecular chaperones, assist it to fold into its native conformation. Correctly folded receptors transit via ER exit sites and are subsequently transported in coatomer protein (COP)II vesicles to the Golgi complex. Further post-translational modification of the hIP may occur in the Golgi complex before the fully mature hIP is targeted to the plasma membrane. P indicates that the hIP may be phosphorylated. (B), terminally misfolded hIPs may, however, be retrotranslocated to the cytosol, possibly through the Sec61 channel. Once the polypeptide chain is accessible in the cytosol, the hIP is polyubiquitinated and, following release from the ER membrane, is degraded by the 26S proteasomes through the ER-associated degradation (ERAD) system. (C), following agonist-induced activation, the mature hIP is internalised into early Rab5a positive-endosomes. From there, it may be (i) recycled to the plasma membrane or (ii) polyubiquitinated which targets it to the late endosomes/multi-vesicular bodies (MVBs) and, thereafter, to the lysosomes for degradation.