Alteration of a single hydrogen bond between class II molecules and peptide results in rapid degradation of class II molecules after invariant chain removal

被引:25
作者
Ceman, S
Wu, SH
Jardetzky, TS
Sant, AJ
机构
[1] Univ Chicago, Dept Pathol, Chicago, IL 60637 USA
[2] Univ Chicago, Comm Immunol, Chicago, IL 60637 USA
[3] Univ Chicago, Comm Canc Biol, Chicago, IL 60637 USA
[4] Northwestern Univ, Dept Biochem Mol Biol & Cell Biol, Evanston, IL 60208 USA
关键词
major histocompatibility complex class II; peptide; hydrogen bond; invariant chain; proteolysis;
D O I
10.1084/jem.188.11.2139
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
To characterize the importance of a highly conserved region of the class II beta chain, we introduced an amino acid substitution that is predicted to eliminate a hydrogen bond formed between the class II molecule and peptide. We expressed the mutated beta chain with a wild-type cr chain in a murine L cell by gene transfection. The mutant class II molecule (81 beta H-) assembles normally in the endoplasmic reticulum and transits the Golgi complex. When invariant chain (Ii) is coexpressed with 81 beta H-, the class II-Ii complex is degraded in the endosomes. Expression of 81 beta H- in the absence of Ii results in a cell surface expressed molecule that is susceptible to proteolysis, a condition reversed by incubation with a peptide known to associate with 81 beta H-. We propose that 81 beta H- is protease sensitive because it is unable to productively associate with most peptides, including classII-associated invariant chain peptides. This model is supported by our data demonstrating protease sensitivity of peptide-free wild-type I-A(d) molecules. Collectively, our results suggest both that the hydrogen bonds formed between the class II molecule and peptide are important for the integrity and stability of the complex, and that empty class II molecules are protease sensitive and degraded in endosomes. One function of DM may be to insure continuous groove occupancy of the class II molecule.
引用
收藏
页码:2139 / 2149
页数:11
相关论文
共 51 条
[1]  
AGRAWAL B, 1994, J IMMUNOL, V152, P965
[2]   INVARIANT CHAIN CLEAVAGE AND PEPTIDE LOADING IN MAJOR HISTOCOMPATIBILITY COMPLEX CLASS-II VESICLES [J].
AMIGORENA, S ;
WEBSTER, P ;
DRAKE, J ;
NEWCOMB, J ;
CRESSWELL, P ;
MELLMAN, I .
JOURNAL OF EXPERIMENTAL MEDICINE, 1995, 181 (05) :1729-1741
[3]   INVARIANT CHAIN CAN FUNCTION AS A CHAPERONE PROTEIN FOR CLASS-II MAJOR HISTOCOMPATIBILITY COMPLEX-MOLECULES [J].
ANDERSON, MS ;
MILLER, J .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1992, 89 (06) :2282-2286
[4]   ALLELIC DIFFERENCES AFFECTING INVARIANT CHAIN DEPENDENCY OF MHC CLASS-II SUBUNIT ASSEMBLY [J].
BIKOFF, EK ;
GERMAIN, RN ;
ROBERTSON, EJ .
IMMUNITY, 1995, 2 (03) :301-310
[5]   STRUCTURE OF THE HUMAN CLASS-I HISTOCOMPATIBILITY ANTIGEN, HLA-A2 [J].
BJORKMAN, PJ ;
SAPER, MA ;
SAMRAOUI, B ;
BENNETT, WS ;
STROMINGER, JL ;
WILEY, DC .
NATURE, 1987, 329 (6139) :506-512
[6]   ROLE FOR INTRACELLULAR PROTEASES IN THE PROCESSING AND TRANSPORT OF CLASS-II HLA ANTIGENS [J].
BLUM, JS ;
CRESSWELL, P .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1988, 85 (11) :3975-3979
[7]   IMPORTANCE OF PEPTIDE AMINO AND CARBOXYL TERMINI TO THE STABILITY OF MHC CLASS-I MOLECULES [J].
BOUVIER, M ;
WILEY, DC .
SCIENCE, 1994, 265 (5170) :398-402
[8]  
BRAUNSTEIN NS, 1990, J IMMUNOL, V145, P1635
[9]   3-DIMENSIONAL STRUCTURE OF THE HUMAN CLASS-II HISTOCOMPATIBILITY ANTIGEN HLA-DR1 [J].
BROWN, JH ;
JARDETZKY, TS ;
GORGA, JC ;
STERN, LJ ;
URBAN, RG ;
STROMINGER, JL ;
WILEY, DC .
NATURE, 1993, 364 (6432) :33-39
[10]   Invariant chain protects class II histocompatibility antigens from binding intact polypeptides in the endoplasmic reticulum [J].
Busch, R ;
Cloutier, I ;
Sekaly, RP ;
Hammerling, GJ .
EMBO JOURNAL, 1996, 15 (02) :418-428