Lectin, mannose-binding 1/multiple coagulation factor deficiency protein 2 (LMAN1-MCFD2) complex is a cargo receptor for the transport of alpha-1 antitrypsin (AAT) from the endoplasmic reticulum to the Golgi apparatus, a new study published in Biochemical Journal found.
The interaction of LMAN1 with an N-glycan of the AAT protein is critical for this process, the authors said. These findings are important for the production of recombinant AAT and the development of new treatments for patients with AAT deficiency (AATD).
Previous research has shown that in cells deficient in LMAN1, AAT secretion is defective. Similarly, in mice that are deficient in LMAN1 and MCFD2, there was a mild decrease in the levels of AAT.
In the present study, a team of researchers led by Bin Zhang, PhD, from the Cleveland Clinic in Ohio has shown that knocking out LMAN1 and MCFD2 in HepG2 and HEK293T cells leads to reduced AAT secretion and high AAT levels inside cells because of a delayed endoplasmic reticulum-to-Golgi transport of AAT.
Read more about experimental therapies for AATD
When they added wild-type LMAN1 or MCFD2 protein, the researchers saw that the secretion defects were rescued in the knock-out cells. However, this did not happen when they used mutant proteins.
In another experiment, the researchers showed that when they eliminated the second glycosylation site of the AAT protein, LMAN1-dependent secretion was also eliminated, suggesting that the AAT protein interacts with the LMAN1 through this site.
The team also showed that the interaction of the AAT protein with LMAN1 is independent of MCFD2. Finally, the secretion of the mutant Z variant of the AAT protein is also LMAN1-dependent.
LMAN1 is a transmembrane lectin. It forms a complex with MCFD2, which is a small soluble protein. The complex then cycles between the endoplasmic reticulum and the Golgi.
Zhang Y, Zhu M, Zheng C, Wei W, Emmer BT, Zhang B. LMAN1-MCFD2 complex is a cargo receptor for the ER-Golgi transport of α1-antitrypsin. Biochem J. 2022;24:BCJ20220055. doi:10.1042/BCJ20220055