Multistep, sequential control of the trafficking and function of the multiple sulfatase deficiency gene product, SUMF1 by PDI, ERGIC-53 and ERp44.
Sulfatase modifying factor 1 (SUMF1) encodes for the formylglicine generating enzyme, which activates sulfatases by modifying a key cysteine residue within their catalytic domains. SUMF1 is mutated in patients affected by multiple sulfatase deficiency, a rare recessive disorder in which all sulfatase activities are impaired. Despite the absence of canonical retention/retrieval signals, SUMF1 is largely retained in the endoplasmic reticulum (ER), where it exerts its enzymatic activity on nascent sulfatases. Part of SUMF1 is secreted and paracrinally taken up by distant cells. Here we show that SUMF1 interacts with protein disulfide isomerase (PDI) and ERp44, two thioredoxin family members residing in the early secretory pathway, and with ERGIC-53, a lectin that shuttles between the ER and the Golgi. Functional assays reveal that these interactions are crucial for controlling SUMF1 traffic and function. PDI couples SUMF1 retention and activation in the ER. ERGIC-53 and ERp44 act downstream, favoring SUMF1 export from and retrieval to the ER, respectively. Silencing ERGIC-53 causes proteasomal degradation of SUMF1, while down-regulating ERp44 promotes its secretion. When over-expressed, each of three interactors favors intracellular accumulation. Our results reveal a multistep control of SUMF1 trafficking, with sequential interactions dynamically determining ER localization, activity and secretion.
Fraldi
Alessandro
A
Telethon Institute of Genetics and Medicine, Naples, Italy.
Zito
Ester
E
Annunziata
Fabio
F
Lombardi
Alessia
A
Cozzolino
Marianna
M
Monti
Maria
M
Spampanato
Carmine
C
Ballabio
Andrea
A
Pucci
Piero
P
Sitia
Roberto
R
Cosma
Maria Pia
MP
D006367:HeLa Cells; D006801:Humans; D037241:Mannose-Binding Lectins / Q000378:metabolism*; D008565:Membrane Proteins / Q000378:metabolism*; D018832:Molecular Chaperones / Q000378:metabolism*; D050862:Oxidoreductases Acting on Sulfur Group Donors; D011134:Polysaccharides / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D019704:Protein Disulfide-Isomerases / Q000378:metabolism*; D021381:Protein Transport; D013429:Sulfatases / Q000032:analysis / Q000378:metabolism*
C451899:ERP44 protein, human; C084004:LMAN1 protein, human; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins; D018832:Molecular Chaperones; D011134:Polysaccharides; D050862:Oxidoreductases Acting on Sulfur Group Donors; C480483:SUMF1 protein, human; D013429:Sulfatases; D046988:Proteasome Endopeptidase Complex; D019704:Protein Disulfide-Isomerases