Laforin-malin complex degrades polyglucosan bodies in concert with glycogen debranching enzyme and brain isoform glycogen phosphorylase.
In Lafora disease (LD), the deficiency of either EPM2A or NHLRC1, the genes encoding the phosphatase laforin and E3 ligase, respectively, causes massive accumulation of less-branched glycogen inclusions, known as Lafora bodies, also called polyglucosan bodies (PBs), in several types of cells including neurons. The biochemical mechanism underlying the PB accumulation, however, remains undefined. We recently demonstrated that laforin is a phosphatase of muscle glycogen synthase (GS1) in PBs, and that laforin recruits malin, together reducing PBs. We show here that accomplishment of PB degradation requires a protein assembly consisting of at least four key enzymes: laforin and malin in a complex, and the glycogenolytic enzymes, glycogen debranching enzyme 1 (AGL1) and brain isoform glycogen phosphorylase (GPBB). Once GS1-synthesized polyglucosan accumulates into PBs, laforin recruits malin to the PBs where laforin dephosphorylates, and malin degrades the GS1 in concert with GPBB and AGL1, resulting in a breakdown of polyglucosan. Without fountional laforin-malin complex assembled on PBs, GPBB and AGL1 together are unable to efficiently breakdown polyglucosan. All these events take place on PBs and in cytoplasm. Deficiency of each of the four enzymes causes PB accumulation in the cytoplasm of affected cells. Demonstration of the molecular mechanisms underlying PB degradation lays a substantial biochemical foundation that may lead to understanding how PB metabolizes and why mutations of either EPM2A or NHLRC1 in humans cause LD. Mutations in AGL1 or GPBB may cause diseases related to PB accumulation.
Center for Cancer and Immunology Research, Children's National Medical Center and George Washington University, 111 Michigan Avenue NW, Washington, DC, 20010, USA, ynliu@childrensnational.org.
Yan
Y
Liu
Li
L
Zeng
Keli
K
Ma
Otto
O
Baba
Pen
P
Zheng
Yang
Y
Liu
Yin
Y
Wang
D000818:Animals; D001921:Brain / Q000201:enzymology*; D002352:Carrier Proteins / Q000032:analysis / Q000378:metabolism*; D045744:Cell Line, Tumor; D005936:Glucans / Q000032:analysis / Q000378:metabolism*; D006004:Glycogen Debranching Enzyme System / Q000032:analysis / Q000378:metabolism*; D024981:Glycogen Phosphorylase / Q000032:analysis / Q000378:metabolism*; D057809:HEK293 Cells; D006801:Humans; D007527:Isoenzymes / Q000032:analysis / Q000378:metabolism; D020192:Lafora Disease / Q000378:metabolism / Q000473:pathology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D054558:Protein Tyrosine Phosphatases, Non-Receptor / Q000032:analysis / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases
D002352:Carrier Proteins; D005936:Glucans; D006004:Glycogen Debranching Enzyme System; D007527:Isoenzymes; C083094:polyglucosan; C478960:NHLRC1 protein, human; D044767:Ubiquitin-Protein Ligases; D024981:Glycogen Phosphorylase; D054558:Protein Tyrosine Phosphatases, Non-Receptor; C114990:EPM2A protein, human