Deficient import of acetyl-CoA into the ER lumen causes neurodegeneration and propensity to infections, inflammation, and cancer.
The import of acetyl-CoA into the ER lumen by AT-1/SLC33A1 is essential for the N(ε)-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.
Department of Medicine.
Yajing
Y
Peng
Department of Medicine.
Mi
M
Li
Department of Pathology.
Ben D
BD
Clarkson
Department of Medicine.
Mariana
M
Pehar
Department of Medical Physics and Waisman Laboratory for Brain Imaging and Behavior, and.
Patrick J
PJ
Lao
Department of Medical Physics and Waisman Laboratory for Brain Imaging and Behavior, and.
Ansel T
AT
Hillmer
Department of Medical Physics and Waisman Laboratory for Brain Imaging and Behavior, and.
Todd E
TE
Barnhart
Department of Medical Physics and Waisman Laboratory for Brain Imaging and Behavior, and.
Bradley T
BT
Christian
Rodent Models Core, Waisman Center, University of Wisconsin-Madison, Madison, Wisconsin 53705, and.
Heather A
HA
Mitchell
Department of Medicine.
Barbara B
BB
Bendlin
Department of Pathology.
Matyas
M
Sandor
Department of Medicine, Geriatric Research Education Clinical Center, VA Medical Center, Madison, Wisconsin 53705 lp1@medicine.wisc.edu.
Luigi
L
Puglielli
D000105:Acetyl Coenzyme A / Q000378:metabolism*; D000107:Acetylation; D000818:Animals; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D007239:Infections / Q000235:genetics / Q000378:metabolism*; D007249:Inflammation / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism*; D009410:Nerve Degeneration / Q000378:metabolism* / Q000473:pathology
D000105:Acetyl Coenzyme A