TY - JOUR
T1 - Proteasome-dependent protein quality control of the peroxisomal membrane protein Pxa1p
AU - Devarajan, S.
AU - Meurer, M.
AU - van Roermund, C. W. T.
AU - Chen, X.
AU - Hettema, E. H.
AU - Kemp, S.
AU - Knop, M.
AU - Williams, C.
PY - 2020/9/1
Y1 - 2020/9/1
N2 - Peroxisomes are eukaryotic organelles that function in numerous metabolic pathways and defects in peroxisome function can cause serious developmental brain disorders such as adrenoleukodystrophy (ALD). Peroxisomal membrane proteins (PMPs) play a crucial role in regulating peroxisome function. Therefore, PMP homeostasis is vital for peroxisome function. Recently, we established that certain PMPs are degraded by the Ubiquitin Proteasome System yet little is known about how faulty/non-functional PMPs undergo quality control. Here we have investigated the degradation of Pxa1p, a fatty acid transporter in the yeast Saccharomyces cerevisiae. Pxa1p is a homologue of the human protein ALDP and mutations in ALDP result in the severe disorder ALD. By introducing two corresponding ALDP mutations into Pxa1p (Pxa1MUT), fused to mGFP, we show that Pxa1MUT-mGFP is rapidly degraded from peroxisomes in a proteasome-dependent manner, while wild type Pxa1-mGFP remains relatively stable. Furthermore, we identify a role for the ubiquitin ligase Ufd4p in Pxa1MUT-mGFP degradation. Finally, we establish that inhibiting Pxa1MUT-mGFP degradation results in a partial rescue of Pxa1p activity in cells. Together, our data demonstrate that faulty PMPs can undergo proteasome-dependent quality control. Furthermore, our observations may provide new insights into the role of ALDP degradation in ALD.
AB - Peroxisomes are eukaryotic organelles that function in numerous metabolic pathways and defects in peroxisome function can cause serious developmental brain disorders such as adrenoleukodystrophy (ALD). Peroxisomal membrane proteins (PMPs) play a crucial role in regulating peroxisome function. Therefore, PMP homeostasis is vital for peroxisome function. Recently, we established that certain PMPs are degraded by the Ubiquitin Proteasome System yet little is known about how faulty/non-functional PMPs undergo quality control. Here we have investigated the degradation of Pxa1p, a fatty acid transporter in the yeast Saccharomyces cerevisiae. Pxa1p is a homologue of the human protein ALDP and mutations in ALDP result in the severe disorder ALD. By introducing two corresponding ALDP mutations into Pxa1p (Pxa1MUT), fused to mGFP, we show that Pxa1MUT-mGFP is rapidly degraded from peroxisomes in a proteasome-dependent manner, while wild type Pxa1-mGFP remains relatively stable. Furthermore, we identify a role for the ubiquitin ligase Ufd4p in Pxa1MUT-mGFP degradation. Finally, we establish that inhibiting Pxa1MUT-mGFP degradation results in a partial rescue of Pxa1p activity in cells. Together, our data demonstrate that faulty PMPs can undergo proteasome-dependent quality control. Furthermore, our observations may provide new insights into the role of ALDP degradation in ALD.
KW - ALD
KW - Peroxisome
KW - Proteasome
KW - Protein degradation
KW - ufd4
UR - http://www.scopus.com/inward/record.url?scp=85084995905&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/j.bbamem.2020.183342
DO - https://doi.org/10.1016/j.bbamem.2020.183342
M3 - Article
C2 - 32416190
SN - 0005-2736
VL - 1862
JO - BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
JF - BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES
IS - 9
M1 - 183342
ER -