Human Molecular Genetics Advance Access originally published online on May 28, 2008
Human Molecular Genetics 2008 17(17):2610-2621; doi:10.1093/hmg/ddn161
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Multistep, sequential control of the trafficking and function of the multiple sulfatase deficiency gene product, SUMF1 by PDI, ERGIC-53 and ERp44
,*1 Telethon Institute of Genetics and Medicine (TIGEM), Via P. Castellino 111, 80131 Naples, Italy 2 CEINGE Advanced Biotechnology and Department of Organic Chemistry and Biochemistry, Federico II University, Via Comunale Margherita 482, 80145 Napoli, Italy 3 Department of Pediatrics, Faculty of Medicine, Federico II University, Via S. Pansini 5, 80131 Naples, Italy 4 DIBIT-HSR, Vita-Salute San Raffaele University, Via Olgettina 58, 20132 Milan, Italy
* To whom correspondence should be addressed. Tel: +39 0816132226; Fax: +39 0815609877; Email: cosma{at}tigem.it
Received February 21, 2008; Revised April 16, 2008; Accepted May 23, 2008
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors and the last two authors as joint Senior Authors.