An N-terminal missense mutation in STX11 causative of FHLA abrogates syntaxin-11 binding to Munc18-2

作者:Muller Martha Lena; Chiang Samuel C C; Meeths Marie; Tesi Bianca; Entesarian Miriam; Nilsson Daniel; Wood Stephanie M; Nordenskjold Magnus; Henter Jan Inge; Naqvi Ahmed; Bryceson Yenan T*
来源:Frontiers in Immunology, 2014, 4: 515.
DOI:10.3389/fimmu.2013.00515

摘要

Familial hemophagocytic lymphohistiocytosis (FHL) is an often-fatal hyperinflammatory disorder caused by autosomal recessive mutations in PRF1, UNC13D, STX11, and STXBP2. We identified a homozygous STX11 mutation, c.173T > C (p.L58P), in three patients presenting clinically with hemophagocytic lymphohistiocytosis from unrelated Pakistani families. The mutation yields an amino acid substitution in the N-terminal Habc domain of syntaxin-11 and resulted in defective natural killer cell degranulation. Notably, syntaxin-11 expression was decreased in patient cells. However, in an ectopic expression system, syntaxin-11 L58P was expressed at levels comparable to wild-type syntaxin-11, but did not bind Munc18-2. Moreover, another N-terminal syntaxin-11 mutant, R4A, also did not bind Munc18-2. Thus, we have identified a novel missense STX11 mutation causative of FHL type 4. The syntaxin-11 R4A and L58P mutations reveal that both the N-terminus and Habc domain of syntaxin-11 are required for binding to Munc18-2, implying similarity to the dynamic binary binding of neuronal syntaxin-1 to Munc18-1.

  • 出版日期2014-1-14