A team of researchers co-led by Jen-Tsan Ashley Chi, MD, PhD, professor in molecular genetics and microbiology, Pei Zhou, PhD, James B. Duke Distinguished Professor of Biochemistry, and Matthew J. Hilton, PhD, associate professor in orthopaedic surgery and cell biology, has uncovered a missing piece in the cell’s chemical toolkit — an enzyme that acts as a crucial “release valve” for sulfation, a process that helps shape cartilage, bone, hormones, and even how some drugs work. Results were published in Nature Chemical Biology
Sulfation works like a biological tag, allowing cells to modify molecules and fine-tune their function. To power this reaction, cells rely on a fuel known as PAPS. For decades, scientists knew how cells produced PAPS but not how they broke it down. That gap has now been filled by the discovery of MESH1, which can accomplish this role.
Chi, Zhou, Hilton, and colleagues identified the human enzyme MESH1 as the long-sought PAPS phosphatase — the enzyme that lowers PAPS levels and controls sulfation. They also solved the 3D structure of MESH1 bound to PAPS. Using mouse models and C. elegans, the team was able to show that MESH1 plays a central role in regulating sulfation in animals. The C. elegans studies were conducted in close collaboration with Dong Yan, PhD, associate professor in molecular genetics and microbiology, whose laboratory led the nematode experiments validating MESH1 function in vivo.
The discovery has promising implications for human health. Because MESH1 reduces sulfation, blocking the enzyme could boost sulfation in conditions where it is too low, such as certain cartilage disorders or osteoarthritis. In mouse models, dialing down MESH1 improved cartilage-related molecules and partially restored bone density. In worms, altering MESH1 helped reduce sulfation-linked neurotoxicity.
“This is a beautiful illustration of how biochemistry and structural biology have advanced our understanding of MESH1’s novel function,” Zhou, who first proposed MESH1’s potential PAPS phosphatase activity based on structural insights, stated.
“These proof-of-concept results point to MESH1 inhibitors as a potential new way to treat sulfation-deficiency conditions,” Chi said. Their next step is to develop selective drugs that block MESH1 and enhance sulfation — opening the door to new therapeutic strategies for bone and cartilage disease.