p97 functions as an auxiliary factor to facilitate TM domain extraction during CFTR ER-associated degradation

被引:49
作者
Carlson, Eric J. [1 ]
Pitonzo, David [1 ]
Skach, William R. [1 ]
机构
[1] Oregon Hlth Sci Univ, Dept Biochem & Mol Biol, Portland, OR 97239 USA
关键词
CFTR; ERAD; ER-associated degradation; polytopic protein; p97;
D O I
10.1038/sj.emboj.7601307
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
The AAA-ATPase ((A) under bar TPase (a) under bar ssociated with various cellular (a) under bar ctivities) p97 has been implicated in the degradation of misfolded and unassembled proteins in the endoplasmic reticulum (ERAD). To better understand its role in this process, we used a reconstituted cell-free system to define the precise contribution of p97 in degrading immature forms of the polytopic, multi-domain protein CFTR (cystic fibrosis transmembrane conductance regulator). Although p97 augmented both the rate and the extent of CFTR degradation, it was not obligatorily required for ERAD. Only a 50% decrease in degradation was observed in the complete absence of p97. Moreover, p97 specifically stimulated the degradation of CFTR transmembrane (TM) domains but had no effect on isolated cytosolic domains. Consistent with this, p97-mediated extraction of intact TM domains was independent of proteolytic cleavage and influenced by TM segment hydrophobicity, indicating that the relative contribution of p97 is partially determined by substrate stability. Thus, we propose that p97 functions in ERAD as a nonessential but important ancillary component to the proteasome where it facilitates substrate presentation and increases the degradation rate and efficiency of stable ( TM) domains.
引用
收藏
页码:4557 / 4566
页数:10
相关论文
共 63 条
  • [11] The F508 cystic fibrosis mutation impairs domain-domain interactions and arrests post-translational folding of CFTR
    Du, K
    Sharma, M
    Lukacs, GL
    [J]. NATURE STRUCTURAL & MOLECULAR BIOLOGY, 2005, 12 (01) : 17 - 25
  • [12] Distinct steps in dislocation of luminal endoplasmic reticulum-associated degradation substrates - Roles of endoplasmic reticulum-bound p97/Cdc48p and proteasome
    Elkabetz, Y
    Shapira, I
    Rabinovich, E
    Bar-Nun, S
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (06) : 3980 - 3989
  • [13] Functional profiling of the Saccharomyces cerevisiae genome
    Giaever, G
    Chu, AM
    Ni, L
    Connelly, C
    Riles, L
    Véronneau, S
    Dow, S
    Lucau-Danila, A
    Anderson, K
    André, B
    Arkin, AP
    Astromoff, A
    El Bakkoury, M
    Bangham, R
    Benito, R
    Brachat, S
    Campanaro, S
    Curtiss, M
    Davis, K
    Deutschbauer, A
    Entian, KD
    Flaherty, P
    Foury, F
    Garfinkel, DJ
    Gerstein, M
    Gotte, D
    Güldener, U
    Hegemann, JH
    Hempel, S
    Herman, Z
    Jaramillo, DF
    Kelly, DE
    Kelly, SL
    Kötter, P
    LaBonte, D
    Lamb, DC
    Lan, N
    Liang, H
    Liao, H
    Liu, L
    Luo, CY
    Lussier, M
    Mao, R
    Menard, P
    Ooi, SL
    Revuelta, JL
    Roberts, CJ
    Rose, M
    Ross-Macdonald, P
    Scherens, B
    [J]. NATURE, 2002, 418 (6896) : 387 - 391
  • [14] The regulatory particle of the Saccharomyces cerevisiae proteasome
    Glickman, MH
    Rubin, DM
    Fried, VA
    Finley, D
    [J]. MOLECULAR AND CELLULAR BIOLOGY, 1998, 18 (06) : 3149 - 3162
  • [15] Cystic fibrosis transmembrane conductance regulator degradation depends on the lectins Htm1p/EDEM and the Cdc48 protein complex in yeast
    Gnann, A
    Riordan, JR
    Wolf, DH
    [J]. MOLECULAR BIOLOGY OF THE CELL, 2004, 15 (09) : 4125 - 4135
  • [16] Apoprotein B degradation is promoted by the molecular chaperones hsp90 and hsp70
    Gusarova, V
    Caplan, AJ
    Brodsky, JL
    Fisher, EA
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (27) : 24891 - 24900
  • [17] The conserved Np14 protein complex mediates proteasome-dependent membrane-bound transcription factor activation
    Hitchcock, AL
    Krebber, H
    Frietze, S
    Lin, A
    Latterich, M
    Silver, PA
    [J]. MOLECULAR BIOLOGY OF THE CELL, 2001, 12 (10) : 3226 - 3241
  • [18] Distinct machinery is required in Saccharomyces cerevisiae for the endoplasmic reticulum-associated degradation of a multispanning membrane protein and a soluble luminal protein
    Huyer, G
    Fansler, Z
    Kreft, SG
    Hochstrasser, M
    Brodsky, JL
    Michaelis, S
    [J]. JOURNAL OF BIOLOGICAL CHEMISTRY, 2004, 279 (37) : 38369 - 38378
  • [19] Protein dislocation from the ER requires polyubiquitination and the AAA-ATPase Cdc48
    Jarosch, E
    Taxis, C
    Volkwein, C
    Bordallo, J
    Finley, D
    Wolf, DH
    Sommer, T
    [J]. NATURE CELL BIOLOGY, 2002, 4 (02) : 134 - 139
  • [20] MULTIPLE PROTEOLYTIC SYSTEMS, INCLUDING THE PROTEASOME, CONTRIBUTE TO CFTR PROCESSING
    JENSEN, TJ
    LOO, MA
    PIND, S
    WILLIAMS, DB
    GOLDBERG, AL
    RIORDAN, JR
    [J]. CELL, 1995, 83 (01) : 129 - 135