Proteasome Inhibitors Block a Late Step in Lysosomal Transport of Selected Membrane but not Soluble Proteins

Kerkhof, Peter van; Santos, Cristina M. Alves dos; Sachse, Martin; Klumperman, Judith; Bu, Guojun; Strous, Ger J.

doi:10.1091/mbc.12.8.2556

Cited by 110 publications

(79 citation statements)

References 54 publications

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“…Very recently, the involvement of both proteasome and lysosomes in the degradation pathway of wt AQP2 in a mouse renal collecting duct cell line was reported. 44 Thus, as observed for other membrane proteins, 45,46 the final degradative pathway for wt AQP2 and misrouted E258K AQP2 seems to involve both the proteasome and lysosomes. However, the T126M AQP2 and the E258K AQP2 expressed in clone 9 hepatocytes seem to be recognized by different quality control mechanisms and become efficiently degraded despite the fact that one is retained in the ER and the other is being misrouted to late endosomes and lysosomes.…”

Section: Discussionmentioning

confidence: 62%

The Proteasome Is Involved in the Degradation of Different Aquaporin-2 Mutants Causing Nephrogenic Diabetes Insipidus

Hirano

Zuber

Roth

et al. 2003

The American Journal of Pathology

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Mutations in the water channel aquaporin-2 (AQP2) can cause congenital nephrogenic diabetes insipidus. To reveal the possible involvement of the protein quality control system in processing AQP2 mutants, we created an in vitro system of clone 9 hepatocytes stably expressing endoplasmic reticulum-retained T126M AQP2 and misrouted E258K AQP2 as well as wild-type AQP2 and studied their biosynthesis, degradation, and intracellular distribution. Mutant and wild-type AQP2 were synthesized as 29-kd nonglycosylated and 32-kd core-glycosylated forms in the endoplasmic reticulum. The wild-type AQP2 had a t 1/2 of 4.6 hours. Remarkable differences in the degradation kinetics were observed for the glycosylated and nonglycosylated T126M AQP2 (t 1/2 ‫؍‬ 2.0 hours versus 0.9 hours). Moreover, their degradation was depending on proteasomal activity as demonstrated in inhibition studies. Degradation of E258K AQP2 also occurred rapidly (t 1/2 ‫؍‬ 1.8 hours) but in a proteasome-and lysosome-dependent manner. By triple confocal immunofluorescence microscopy misrouting of E258K to lysosomes via the Golgi apparatus could be demonstrated. Notwithstanding the differences in degradation kinetics and subcellular distribution such as endoplasmic reticulum-retention and misrouting to lysosomes, both T126M and E258K AQP2 were efficiently degraded. This implies the involvement of different protein quality control processes in the processing of these AQP2 mutants. The endoplasmic reticulum (ER) represents a site of quality control of glycoprotein folding. 1,2 Misfolded glycoproteins are recognized and retained by the concerted action of chaperones, lectins, and modifying enzymes such as UDP-glucose:glycoprotein glucosyltransferase and glucosidase II. 3 Glycoproteins failing to achieve their correct conformation might become retrotranslocated to the cytosol 4 and degraded by the ubiquitin-proteasome pathway, a process referred to as ER-associated protein degradation. [5][6][7] Quality control of protein folding is of importance in congenital diseases caused by point mutations that result in the synthesis of misfolded glycoproteins. 8 Mutations in the water channel aquaporin-2 (AQP2) can cause nephrogenic diabetes insipidus (NDI), in which patients are unable to concentrate urine in response to the anti-diuretic hormone arginine-vasopressin. 9 -11 If not corrected, this defect results in a deregulated whole-body water homeostasis that is accompanied by various symptoms of dehydration. 12 AQP2 belongs to the large family of AQPs, 13,14 and is a 29-kd polytope membrane protein that contains a single N-glycosylation site and two phosphorylation sites, and is present in the principal cells of renal collecting ducts. 15,16 In states of hypernatremia or hypovolemia, translocation of phosphorylated AQP2 homotetramers from vesicles to the apical plasma membrane of the principal cells is triggered by a signal transduction cascade induced by arginine-vasopressin. 16 -18 Alike to normal human kidney, 19 wild-type (wt) AQP2, when expressed in Xenopus ooc...

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Section: Discussionmentioning

confidence: 62%

The Proteasome Is Involved in the Degradation of Different Aquaporin-2 Mutants Causing Nephrogenic Diabetes Insipidus

Hirano

Zuber

Roth

et al. 2003

The American Journal of Pathology

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“…Because the binding site of CHIP extends downstream of amino acid 334, it might mean that removing this binding site also would eliminate the necessity of CHIP. This is reminiscent of the involvement of the proteasome: its action is required for the endocytosis of the full-length receptor but is dispensable for a receptor truncated after amino acid amino acid 366 (55). However, the GHR truncated at 334 might still have sufficient binding affinity for CHIP to act as a necessary factor for endocytosis of the GHR334.…”

Section: Discussionmentioning

confidence: 99%

Ubc13 and COOH Terminus of Hsp70-interacting Protein (CHIP) Are Required for Growth Hormone Receptor Endocytosis

Slotman

Almeida

Hassink

et al. 2012

Journal of Biological Chemistry

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Background:The scientific question that we address is how cytokine receptors organize their degradation. Results: CHIP and Ubc13 are required for GH receptor endocytosis, implicating Lys 63 -specific ubiquitination. Conclusion: This study shows how two ubiquitin ligases act in concert to allow receptor endocytosis. Significance: Understanding this mechanism enables drug design to control GH signaling in fighting cancer and cachexia.

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“…Bars, 20 m. Representative images from three independent experiments are shown. endocytic pathway (37,38,39,40). One suggested mechanism proposes that the inhibition of proteasome activity interferes with transport by perturbing the requisite protein mono-ubiquitination cycle due to decreased availability of free ubiquitin and increased steady state accumulation of mono-and multiubiquitinated proteins.…”

Section: Figmentioning

confidence: 99%

The Proteasome α-Subunit XAPC7 Interacts Specifically with Rab7 and Late Endosomes

Dong

Chen

Welford

et al. 2004

Journal of Biological Chemistry

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Rab7 is a key regulatory protein governing early to late endocytic membrane transport. In this study the proteasome ␣-subunit XAPC7 (also known as PSMA7, RC6 -1, and HSPC in mammals) was identified to interact specifically with Rab7 and was recruited to multivesicular late endosomes through this interaction. The protein interaction domains were localized to the C terminus of XAPC7 and the N terminus of Rab7. XAPC7 was not found on early or recycling endosomes, but could be recruited to recycling endosomes by expression of a Rab7-(1-174)Rab11-(160 -202) chimera, establishing a central role for Rab7 in the membrane recruitment of XAPC7. Although XAPC7 could be shown to associate with membranes bearing ubiquitinated cargo, overexpression had no impact on steady-state ubiquitinated protein levels. Most notably, overexpression of XAPC7 was found to impair late endocytic transport of two different membrane proteins, including EGFR known to be highly dependent on ubiquitination and proteasome activity for proper endocytic sorting and lysosomal transport. Decreased late endocytic transport caused by XAPC7 overexpression was partially rescued by coexpression of wild-type Rab7, suggesting a negative regulatory role for XAPC7. Nevertheless, Rab7 itself was not subject to XAPC7-dependent proteasomal degradation. Together the data establish the first direct molecular link between the endocytic trafficking and cytosolic degradative machineries.

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Proteasome Inhibitors Block a Late Step in Lysosomal Transport of Selected Membrane but not Soluble Proteins

Cited by 110 publications

References 54 publications

The Proteasome Is Involved in the Degradation of Different Aquaporin-2 Mutants Causing Nephrogenic Diabetes Insipidus

The Proteasome Is Involved in the Degradation of Different Aquaporin-2 Mutants Causing Nephrogenic Diabetes Insipidus

Ubc13 and COOH Terminus of Hsp70-interacting Protein (CHIP) Are Required for Growth Hormone Receptor Endocytosis

The Proteasome α-Subunit XAPC7 Interacts Specifically with Rab7 and Late Endosomes

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