Abstract
The efficient clearance of cytotoxic misfolded protein aggregates is critical for cell survival. Misfolded protein aggregates are transported and removed from the cytoplasm by dynein motors via the microtubule network to a novel organelle termed the aggresome where they are processed. However, the means by which dynein motors recognize misfolded protein cargo, and the cellular factors that regulate aggresome formation, remain unknown. We have discovered that HDAC6, a microtubule-associated deacetylase, is a component of the aggresome. We demonstrate that HDAC6 has the capacity to bind both polyubiquitinated misfolded proteins and dynein motors, thereby acting to recruit misfolded protein cargo to dynein motors for transport to aggresomes. Indeed, cells deficient in HDAC6 fail to clear misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly, and are hypersensitive to the accumulation of misfolded proteins. These findings identify HDAC6 as a crucial player in the cellular management of misfolded protein-induced stress.
| Original language | English |
|---|---|
| Pages (from-to) | 727-738 |
| Number of pages | 12 |
| Journal | Cell |
| Volume | 115 |
| Issue number | 6 |
| DOIs | |
| State | Published - Dec 12 2003 |
| Externally published | Yes |
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ASJC Scopus subject areas
- Cell Biology
- Molecular Biology
Cite this
The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. / Kawaguchi, Yoshiharu; Kovacs, Jeffrey J.; McLaurin, Adam; Vance, Jeffery M; Ito, Akihiro; Yao, Tso Pang.
In: Cell, Vol. 115, No. 6, 12.12.2003, p. 727-738.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress
AU - Kawaguchi, Yoshiharu
AU - Kovacs, Jeffrey J.
AU - McLaurin, Adam
AU - Vance, Jeffery M
AU - Ito, Akihiro
AU - Yao, Tso Pang
PY - 2003/12/12
Y1 - 2003/12/12
N2 - The efficient clearance of cytotoxic misfolded protein aggregates is critical for cell survival. Misfolded protein aggregates are transported and removed from the cytoplasm by dynein motors via the microtubule network to a novel organelle termed the aggresome where they are processed. However, the means by which dynein motors recognize misfolded protein cargo, and the cellular factors that regulate aggresome formation, remain unknown. We have discovered that HDAC6, a microtubule-associated deacetylase, is a component of the aggresome. We demonstrate that HDAC6 has the capacity to bind both polyubiquitinated misfolded proteins and dynein motors, thereby acting to recruit misfolded protein cargo to dynein motors for transport to aggresomes. Indeed, cells deficient in HDAC6 fail to clear misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly, and are hypersensitive to the accumulation of misfolded proteins. These findings identify HDAC6 as a crucial player in the cellular management of misfolded protein-induced stress.
AB - The efficient clearance of cytotoxic misfolded protein aggregates is critical for cell survival. Misfolded protein aggregates are transported and removed from the cytoplasm by dynein motors via the microtubule network to a novel organelle termed the aggresome where they are processed. However, the means by which dynein motors recognize misfolded protein cargo, and the cellular factors that regulate aggresome formation, remain unknown. We have discovered that HDAC6, a microtubule-associated deacetylase, is a component of the aggresome. We demonstrate that HDAC6 has the capacity to bind both polyubiquitinated misfolded proteins and dynein motors, thereby acting to recruit misfolded protein cargo to dynein motors for transport to aggresomes. Indeed, cells deficient in HDAC6 fail to clear misfolded protein aggregates from the cytoplasm, cannot form aggresomes properly, and are hypersensitive to the accumulation of misfolded proteins. These findings identify HDAC6 as a crucial player in the cellular management of misfolded protein-induced stress.
UR - http://www.scopus.com/inward/record.url?scp=0346020435&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=0346020435&partnerID=8YFLogxK
U2 - 10.1016/S0092-8674(03)00939-5
DO - 10.1016/S0092-8674(03)00939-5
M3 - Article
C2 - 14675537
AN - SCOPUS:0346020435
VL - 115
SP - 727
EP - 738
JO - Cell
JF - Cell
SN - 0092-8674
IS - 6
ER -