乙酰化介导白念珠菌NuA4和SWR1复合物的分离与整合在菌丝发育和酵母态维持中的调控机制

Candida albicans is able to undergo reversible morphological changes between yeast and hyphal forms of growth in response to environmental cues and can successfully infect many different anatomical sites of the human host. Its morphological plasticity is the most important virulence attribute of C. albicans. NuA4 (Nucleosome acetyltransferase of H4) complex is highly conserved HAT in eukaryotes and plays important roles in cell transformation, development, transcription and DNA repair. SWR1 complex is an ATP-dependent remodeling complex required for deposition of histone variants. Based on the Candida Genome database, C. albicans NuA4 complex composes of 12 subunits and SWR1 complex composes of 15 subunits. To elucidate the role of C. albicans NuA4 and SWR1 complexes in cell growth and morphogenesis, we deleted all the components in the NuA4 and SWR1 complexes. Different to the other Esa1 orthologues, the C. albicans Esa1, the core catalytic enzyme in the NuA4 complex is not essential for general growth, but is essential for hyphal development and virulence in a systemic infection. On the other hand, the Swr1, the core catalytic enzyme in the SWR1 complex is essential for yeast growth. Our study will focus on Molecular and cellular mechanism of NuA4 and SWR1 complexes in C. albicans morphorgenesis and pathogenesis. Furthermore, we will analyze the integration and separation of the NuA4 acetyl-transferase complex and SWR1 remodeling complex in global level during the reversible morphological transition and demonstrate functional roles of Esa1 mediated acetylation of the multiple substrates on the yeast growth and hyphal development. The dynamic association and dissociation between NuA4 and SWR1 complexes in global level may add a new layer to general mechanism in the regulation of proliferation and differentiation for higher eukaryotes.

白念珠菌酵母菌丝形态的可逆转换能力与其在人体内繁殖和侵染能力成正比。从基因组序列推测白念珠菌NuA4乙酰转移酶复合物包含12个成员，而SWR1染色质重塑复合物包含15个成员。我们已经鉴定了这两个复合物的多个成员，功能各异；NuA4核心酶基因ESA1的敲除并不致死，而是为菌丝发育所必须，参与系统感染致病过程；SWR1核心酶SWR1基因的敲除也不致死，但是为酵母维持所必须。我们首次证明这两个复合物在可逆的酵母菌丝转换过程能够融合和分离，调控白念珠菌的菌丝发育和酵母态生长。因此，本项目研究内容包括：1、NuA4复合物成员在菌丝发育中的功能作用；2、SWR1复合物成员在酵母态维持中的功能作用；3、NuA4和SWR1复合物白念珠菌系统感染中的功能作用；4、NuA4和SWR1复合物的分离与整合调控酵母菌丝形态转换的机制；5、Esa1催化多底物乙酰化调控菌丝发育和酵母态维持中的分子和细胞机制。