Abstract
Abstract Several studies on disposal of nonsecreted Ig L chains have identified the endoplasmic reticulum as the site of degradation. Here, we examine degradation of a nonsecreted Ig L chain, T15L, and an experimentally endoplasmic reticulum-retained secretion-competent L chain, D16L, in the absence of H chains. We demonstrate that 1) degradation is specifically impaired by the proteasome-specific inhibitors carboxybenzyl-leucyl-leucyl-leucine vinyl sulfone (Z-L3VS) and lactacystin, 2) L chain degradation occurs early in the biosynthetic pathway, and 3) degradation does not require vesicular transport. Our findings indicate that previous assertions of L chain disposal within the endoplasmic reticulum must be modified. To our knowledge, we provide the first direct evidence supporting a new paradigm for removal of nonsecreted Ig L chains via dislocation to cytosolic proteasomes.
References
27
Referenced
18
-
Ward, C. L., S. Omura, R. R. Kopito. 1995. Degradation of CFTR by the ubiquitin-proteasome pathway. Cell 83: 121
(
10.1016/0092-8674(95)90240-6
) -
Biederer, T., C. Volkwein, T. Sommer. 1996. Degradation of subunits of the Sec61p complex, an integral component of the ER membrane, by the ubiquitin-proteasome pathway. EMBO J. 15: 2069
(
10.1002/j.1460-2075.1996.tb00560.x
) -
Hughes, E. A., C. Hammond, P. Cresswell. 1997. Misfolded major histocompatibility complex class I heavy chains are translocated into the cytoplasm and degraded by the proteasome. Proc. Natl. Acad. Sci. USA 94: 1896
(
10.1073/pnas.94.5.1896
) -
Wiertz, E. J. H. J., T. R. Jones, L. Sun, M. Bogyo, H. J. Geuze, H. L. Ploegh. 1996. The human cytomegalovirus US11 gene product dislocates MHC class I heavy chains from the endoplasmic reticulum to the cytosol. Cell 84: 769
(
10.1016/S0092-8674(00)81054-5
) -
McCracken, A. A., J. L. Brodsky. 1996. Assembly of ER-associated protein degradation in vitro: dependence on cytosol, calnexin, and ATP. J. Cell Biol. 132: 291
(
10.1083/jcb.132.3.291
) -
Qu, D., J. H. Teckman, S. Omura, D. H. Perlmutter. 1996. Degradation of a mutant secretory protein, α1-antitrypsin Z, in the endoplasmic reticulum requires proteasome activity. J. Biol. Chem. 271: 22791
(
10.1074/jbc.271.37.22791
) -
Hiller, M. M., A. Finger, M. Schweiger, D. H. Wolf. 1996. ER degradation of a misfolded luminal protein by the cytosolic ubiquitin-proteasome pathway. Science 273: 1725
(
10.1126/science.273.5282.1725
) -
Meerovitch, K., S. Wing, D. Goltzman. 1998. Proparathyroid hormone-related protein is associated with the chaperone protein BiP and undergoes proteasome-mediated degradation. J. Biol. Chem. 273: 21025
(
10.1074/jbc.273.33.21025
) -
Benoist, F., T. Grand-Perret. 1997. Co-translational degradation of apolipoprotein B100 by the proteasome is prevented by microsomal triglyceride transfer protein: synchronized translation studies on HepG2 cells treated with an inhibitor of microsomal triglyceride transfer protein. J. Biol. Chem. 272: 20435
(
10.1074/jbc.272.33.20435
) -
Yeung, S. J., S. H. Chen, L. Chan. 1996. Ubiquitin-proteasome pathway mediates intracellular degradation of apolipoprotein B. Biochemistry 35: 13843
(
10.1021/bi9618777
) -
Reddy, P., A. Sparvoli, C. Fagioli, G. Fassina, R. Sitia. 1996. Formation of reversible disulfide bonds with the protein matrix of the endoplasmic reticulum correlates with the retention of unassembled Ig light chains. EMBO J. 15: 2077
(
10.1002/j.1460-2075.1996.tb00561.x
) -
Sitia, R., M. Neuberger, C. Alberini, P. Bet, A. Fra, C. Valetti, G. Williams, C. Milstein. 1990. Developmental regulation of IgM secretion: the role of the carboxy-terminal cysteine. Cell 60: 781
(
10.1016/0092-8674(90)90092-S
) -
Winitz, D., I. Shachar, Y. Elkabetz, R. Amitay, M. Samuelov, S. Bar-Nun. 1996. Degradation of distinct assembly forms of immunoglobulin M occurs in multiple sites in permeabilized B cells. J. Biol. Chem. 271: 27645
(
10.1074/jbc.271.44.27645
) -
Chen, C., T. M. Martin, S. Stevens, M. B. Rittenberg. 1994. Defective secretion of an immunoglobulin caused by mutations in the heavy chain complementary determining region 2. J. Exp. Med. 180: 577
(
10.1084/jem.180.2.577
) -
Wiens, G. D., K. A. Heldwein, M. P. Stenzel-Poore, M. B. Rittenberg. 1997. Somatic mutation in VH complementarity-determining region 2 and framework region 2: differential effects on antigen binding and Ig secretion. J. Immunol. 159: 1293
(
10.4049/jimmunol.159.3.1293
) -
Martin, T. M., G. D. Wiens, M. B. Rittenberg. 1998. Inefficient assembly and intracellular accumulation of antibodies with mutations in VH CDR2. J. Immunol. 160: 5963
(
10.4049/jimmunol.160.12.5963
) -
Chen, C., V. A. Roberts, M. B. Rittenberg. 1992. Generation and analysis of random point mutations in an antibody CDR2 sequence: many mutated antibodies lose their ability to bind antigen. J. Exp. Med. 176: 855
(
10.1084/jem.176.3.855
) -
Stenzel-Poore, M. P., U. Bruderer, M. B. Rittenberg. 1988. The adaptive potential of the memory response: clonal recruitment and epitope recognition. Immunol. Rev. 105: 114
(
10.1111/j.1600-065X.1988.tb00769.x
) -
Neumann, E., M. Schaefer-Ridder, Y. Wang, P. H. Hofschneider. 1982. Gene transfer into mouse lyoma cells by electroporation in high electric fields. EMBO J. 1: 841
(
10.1002/j.1460-2075.1982.tb01257.x
) -
Martin, T. M., C. Kowalczyk, S. Stevens, G. D. Wiens, M. P. Stenzel-Poore, M. B. Rittenberg. 1996. Deletion in HCDR3 rescues T15 antibody mutants from a secretion defect caused by mutations in HCDR2. J. Immunol. 157: 4341
(
10.4049/jimmunol.157.10.4341
) -
Beersma, M. F. C., M. J. E. Bijlmakers, H. L. Ploegh. 1993. Human cytomegalovirus down-regulates HLA class I expression by reducing the stability of class I heavy chains. J. Immunol. 151: 4455
(
10.4049/jimmunol.151.9.4455
) -
Gardner, A. M., S. Aviel, Y. Argon. 1993. Rapid degradation of an unassembled immunoglobulin light chain is mediated by a serine protease and occurs in a pre-Golgi compartment. J. Biol. Chem. 268: 25940
(
10.1016/S0021-9258(19)74477-9
) -
Knittler, M. R., S. Dirks, I. G. Haas. 1995. Molecular chaperones involved in protein degradation in the endoplasmic reticulum: quantitative interaction of the heat shock cognate protein BiP with partially folded immunoglobulin light chains that are degraded in the endoplasmic reticulum. Proc. Natl. Acad. Sci. USA 92: 1764
(
10.1073/pnas.92.5.1764
) -
Kurachi, S., D. P. Pantazatos, K. Kurachi. 1997. The carboxyl-terminal region of factor IX is essential for its secretion. Biochemistry 36: 4337
(
10.1021/bi962002v
) -
Lippincott-Schwartz, J., J. S. Bonifacino, L. C. Yuan, R. D. Klausner. 1988. Degradation from the endoplasmic reticulum: disposing of newly synthesized proteins. Cell 54: 209
(
10.1016/0092-8674(88)90553-3
) -
Yu, H., G. Kaung, S. Kobayashi, R. R. Kopito. 1997. Cytosolic degradation of T-cell receptor α chains by the proteasome. J. Biol. Chem. 272: 20800
(
10.1074/jbc.272.33.20800
) -
Skowronek, M. H., L. M. Hendershot, I. G. Haas. 1998. The variable domain of nonassembled Ig light chains determines both their half-life and binding to the chaperone BiP. Proc. Natl. Acad. Sci. USA 95: 1574
(
10.1073/pnas.95.4.1574
)
Dates
Type | When |
---|---|
Created | 2 years, 7 months ago (Jan. 1, 2023, 12:31 p.m.) |
Deposited | 7 months, 3 weeks ago (Jan. 2, 2025, 1:17 p.m.) |
Indexed | 7 months, 3 weeks ago (Jan. 3, 2025, 12:33 a.m.) |
Issued | 26 years, 1 month ago (July 1, 1999) |
Published | 26 years, 1 month ago (July 1, 1999) |
Published Print | 26 years, 1 month ago (July 1, 1999) |
@article{O_Hare_1999, title={Cutting Edge: Proteasome Involvement in the Degradation of Unassembled Ig Light Chains}, volume={163}, ISSN={1550-6606}, url={http://dx.doi.org/10.4049/jimmunol.163.1.11}, DOI={10.4049/jimmunol.163.1.11}, number={1}, journal={The Journal of Immunology}, publisher={Oxford University Press (OUP)}, author={O’Hare, Thomas and Wiens, Gregory D. and Whitcomb, Elizabeth A. and Enns, Caroline A. and Rittenberg, Marvin B.}, year={1999}, month=jul, pages={11–14} }