REGULATION OF DRUG TRANSPORTER ACTIVITY - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 521

Cell membrane

Transporters

Transporters Transporters

Ub

(Ub)n

Ub

Ub

Golgi

Endosome

Transporters

Ub

Transporters

ER

Proteasome
degradation

Misfold
(Quality Control)

Lysosome
degradation

Transporters

(Ub)n

FIGURE 17.2. Ubiquitin-dependent degradation pathways of transporters. Polyubiquitinated
transporters from the membrane will be degraded within proteasome. Misfolded proteins can
also be ubiquitinated and removed by proteasome degradation. The mono-ubiquinated trans-
porter proteins, on the other hand, would be degraded through the lysome pathway. Ub, ubiq-
uitin; (Ub)n, ubiquitin polymers.

reticulum. 16 The lysosome degrades membrane proteins and extracellular materials
that enter the cell via endocytosis. 15 Ubiquitin-mediated degradation usually occurs
in proteasome. It was found 17 that in drug-resistant cancer cells, P-glycoprotein was
ubiquitinated constitutively. Transfection of multidrug-resistant cells with wild-type
ubiquitin increased the ubiquitination of P-glycoprotein and increased its degradation.
Proteasome inhibitor MG-132 induced accumulation of ubiquitinated P-glycoprotein,
suggesting involvement of the proteasome in turnover of the transporter. Enhanced
ubiquitination of P-glycoprotein resulted in reduced function of the transporter, as
demonstrated by increased intracellular drug accumulation and increased cellular
sensitivity to drugs transported by P-glycoprotein.
In the cholangiocytes of liver, apical sodium-dependent bile acid transporter
(ASBT) was found to be a short-lived protein and was associated with ubiquitin. 18 The
inflammatory cytokine interleukin-1 ) induced down-regulation of ASBT ex-

pression. Such down-regulation was accompanied by an increase in ABST polyubiq-
uitin conjugates and a reduced ASBT half-life. However, in phosphorylation-deficient
mutants, the ASBT half-life is prolonged markedly, IL-1

(IL-1

-induced ASBT ubiquiti-

nation is reduced significantly, and IL-1 failed to increase ASBT degradation. These

results indicated that ASBT undergoes ubiquitin-mediated degradation under basal
conditions, and such degradation is increased by IL-1 due to the serine/threonine

phosphorylation of the transporter.