Immunity-related GTPase M (IRGM) Proteins Influence the Localization of Guanylate-binding Protein 2 (GBP2) by Modulating Macroautophagy
Immunity-related GTPase M (IRGM) Proteins Influence the Localization of Guanylate-binding Protein 2 (GBP2) by Modulating Macroautophagy
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DOI：
10.1074/jbc.m111.251967
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发表时间：
2011-09-02
影响因子：
4.8
通讯作者：
Taylor, Gregory A.
中科院分区：
文献类型：
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作者：
Traver, Maria K.;Henry, Stanley C.;Taylor, Gregory A.
免疫相关GTP酶（IRGs）是由干扰素-γ诱导的蛋白质家族，其在对细胞内病原体的先天抗性中起关键作用。IRG蛋白的M亚家族（IRGM）在这方面起着重要的作用，部分原因是其成员能够调节其他IRG蛋白的定位和表达。我们在这里提供的证据表明，IRGM蛋白影响鸟苷酸结合蛋白（GBP）的定位，鸟苷酸结合蛋白是干扰素诱导的第二个GT结合蛋白家族，也在先天免疫中发挥作用。Irgm 1或Irgm 3的缺失导致Gbp 2在细胞内区室中的积累，所述细胞内区室对大自噬（下文称为自噬）标记物LC 3和自噬衔接分子p62/Sqstm 1均呈阳性。Gbp 2同样重新定位在细胞中，其中自噬受损，因为缺乏Atg 5。在Atg 5和IRGM缺陷细胞中，IRG蛋白Irga 6重新定位于与Gbp 2相同的隔室，这提高了共同调控机制的可能性。然而，其他数据表明，Irga 6，而不是Gbp 2，在IRGM缺陷细胞中被泛素化。类似地，免疫共沉淀研究表明，虽然Irgm 3确实与Irgb 6直接相互作用，但它不与Gbp 2相互作用。总的来说，这些数据表明，IRGM蛋白间接调节GBP的本地化通过一个不同的机制，通过它们调节IRG蛋白的本地化。此外，这些结果表明，IRGM蛋白的核心功能是调节自噬通量，其影响GBP的定位和可能的其他指示细胞自主免疫抗性的因素。
The immunity-related GTPases (IRGs) are a family of proteins induced by interferon-gamma that play a crucial role in innate resistance to intracellular pathogens. The M subfamily of IRG proteins (IRGM) plays a profound role in this context, in part because of the ability of its members to regulate the localization and expression of other IRG proteins. We present here evidence that IRGM proteins affect the localization of the guanylate-binding proteins (GBPs), a second family of interferon-induced GTP-binding proteins that also function in innate immunity. Absence of Irgm1 or Irgm3 led to accumulation of Gbp2 in intracellular compartments that were positive for both the macroautophagy (hereafter referred to as autophagy) marker LC3 and the autophagic adapter molecule p62/Sqstm1. Gbp2 was similarly relocalized in cells in which autophagy was impaired because of the absence of Atg5. Both in Atg5- and IRGM-deficient cells, the IRG protein Irga6 relocalized to the same compartments as Gbp2, raising the possibility of a common regulatory mechanism. However, other data indicated that Irga6, but not Gbp2, was ubiquitinated in IRGM-deficient cells. Similarly, coimmunoprecipitation studies indicated that although Irgm3 did interact directly with Irgb6, it did not interact with Gbp2. Collectively, these data suggest that IRGM proteins indirectly modulate the localization of GBPs through a distinct mechanism from that through which they regulate IRG protein localization. Further, these results suggest that a core function of IRGM proteins is to regulate autophagic flux, which influences the localization of GBPs and possibly other factors that instruct cell-autonomous immune resistance.