TY - JOUR
T1 - Deficient import of Acetyl-CoA into the ER lumen causes neurodegeneration and propensity to infections, inflammation, and cancer
AU - Peng, Yajing
AU - Li, Mi
AU - Clarkson, Ben D.
AU - Pehar, Mariana
AU - Lao, Patrick J.
AU - Hillmer, Ansel T.
AU - Barnhart, Todd E.
AU - Christian, Bradley T.
AU - Mitchell, Heather A.
AU - Bendlin, Barbara B.
AU - Sandor, Matyas
AU - Puglielli, Luigi
PY - 2014
Y1 - 2014
N2 - The import of acetyl-CoA into the ER lumen by AT-1/SLC33A1 is essential for the Nε-lysine acetylation of ER-resident and ER-transiting proteins. A point-mutation (S113R) in AT-1 has been associated with a familial form of spastic paraplegia. Here, we report that AT-1S113R is unable to form homodimers in the ER membrane and is devoid of acetyl-CoA transport activity. The reduced influx of acetyl-CoA into the ER lumen results in reduced acetylation of ER proteins and an aberrant form of autophagy. Mice homozygous for the mutation display early developmental arrest. In contrast, heterozygous animals develop to full term, but display neurodegeneration and propensity to infections, inflammation, and cancer. The immune and cancer phenotypes are contingent on the presence of pathogens in the colony, whereas the nervous system phenotype is not. In conclusion, our results reveal a previously unknown aspect of acetyl-CoA metabolism that affects the immune and nervous systems and the risk for malignancies.
AB - The import of acetyl-CoA into the ER lumen by AT-1/SLC33A1 is essential for the Nε-lysine acetylation of ER-resident and ER-transiting proteins. A point-mutation (S113R) in AT-1 has been associated with a familial form of spastic paraplegia. Here, we report that AT-1S113R is unable to form homodimers in the ER membrane and is devoid of acetyl-CoA transport activity. The reduced influx of acetyl-CoA into the ER lumen results in reduced acetylation of ER proteins and an aberrant form of autophagy. Mice homozygous for the mutation display early developmental arrest. In contrast, heterozygous animals develop to full term, but display neurodegeneration and propensity to infections, inflammation, and cancer. The immune and cancer phenotypes are contingent on the presence of pathogens in the colony, whereas the nervous system phenotype is not. In conclusion, our results reveal a previously unknown aspect of acetyl-CoA metabolism that affects the immune and nervous systems and the risk for malignancies.
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U2 - 10.1523/JNEUROSCI.0077-14.2014
DO - 10.1523/JNEUROSCI.0077-14.2014
M3 - Article
C2 - 24828632
AN - SCOPUS:84900421936
SN - 0270-6474
VL - 34
SP - 6772
EP - 6789
JO - Journal of Neuroscience
JF - Journal of Neuroscience
IS - 20
ER -