Consider a cell surface receptor that upon ligand binding, becomes mono-ubiquiti

Question

Consider a cell surface receptor that upon ligand binding, becomes mono-ubiquitinated, undergoes endocytosis, and finally degradation via the multivesicular body pathway. You probe the system using siRNA to deplete cells of various components and observe the following experimental outcomes. (give detail explanation of each experimental observation)

(1) Knocking down either the the relevant ubiquitin ligase or Hrs or tsg101 causes a lack of degradation of the receptor. Confusingly, the receptor continues to undergo rapid endocytosis upon stimulation, but steady-state surface levels of the receptor are only negligibly reduced.

(2) Knocking down various other components of ESCRT1, ESCRT2, or ESCRT3 results in permanent removal of receptor from the plasma membrane. However, it still does not get degraded. Instead it accumulates intracellularly.

(3) Knocking down vps4 causes a complex phenotype. The receptor undergoes endocytosis upon stimulation as nor- mal. Initially there is some receptor degradation indicated by a slight drop in the total cellular receptor level. However, after this the total receptor population is stable and oddly, as in part 1, at steady state almost 100% of the receptor population is found on the cell surface.

Explanation / Answer

The addition of ubiquitin to a substrate protein is called ubiquitination and single ubiquitin protein attached is called monoubiquitination. Ubiquitination is processed in three main steps: activation, conjugation, and ligation. ligation step is carried out by ubiquitin ligases.

(1) Endocytosis regulates cell signalling by controlling the number of receptors available for activation in the plasma membrane. Stimulation causes activation of receptors or downstream effectors .Thus, undergo rapid endocytosis upon stimulation.However, According to study conducted by M. GEX-FABRY AND C. DELISI ligand binding is independent of receptor recycling in a steady state. Therefore steady-state surface levels of the receptor are only negligibly reduced.

(2) If receptor protein is a tissue- and stage-specific promoter then knocking down receptors may result in removal of receptor from plasma membrane but it may accumulates intracellularly.

(3) The ligand-induced endocytosis is a process to enhance the accuracy of signaling receptors rather than merely serving to attenuate signaling. at steady state the internalization and release of receptors is at equilibrium thus almost 100% of the receptor population is found on the cell surface.

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