Crystal Structures of Membrane Transporter MmpL3, anAnti-TB Drug Target.

Rimonabant purchased from MCE.

盡管為了發(fā)現(xiàn)根除肺結(jié)核病的高效治療方法已經(jīng)進(jìn)行了大量努力，但肺結(jié)核仍然是全球人類健康的一重大威脅。因此，針對(duì)新靶點(diǎn)的新結(jié)核病藥物備受期待。分歧桿菌膜蛋白是近年來(lái)出現(xiàn)的最重要的治療藥物靶點(diǎn)之一，它在脂質(zhì)、高分子、免疫調(diào)節(jié)劑轉(zhuǎn)運(yùn)中占有至關(guān)重要的作用。本文報(bào)道了單獨(dú)的分枝桿菌 MmpL3 晶體結(jié)構(gòu)，以及與 4 種結(jié)核病候選藥物 (包括 SQ109 (處于 2b - 3 期臨床試驗(yàn))的復(fù)合物。MmpL3 由質(zhì)周孔結(jié)構(gòu)域和 12 螺旋跨膜結(jié)構(gòu)域組成。位于該區(qū)域中心的兩個(gè) Asp-Tyr 對(duì)似乎是質(zhì)子易位的關(guān)鍵促進(jìn)因子。SQ109、AU1235、ICA38 和利莫那班在跨膜區(qū)域內(nèi)結(jié)合并破壞這些 Asp-Tyr 配對(duì)體。這些結(jié)構(gòu)數(shù)據(jù)將極大地促進(jìn) MmpL3 抑制劑作為新型結(jié)核病藥物的開(kāi)發(fā)工作。
MmpLs(Mycobacterial membrane proteins Large), which play crucial roles intransporting lipids, polymers and immunomodulators. MmpL3 consists of a periplasmic pore domain and a twelve-helix transmembranedomain. Two Asp-Tyr pairs centrally located in this domain appear to be key facilitators of proton-translocation. SQ109, AU1235, ICA38, and rimonabant bind inside the transmembrane region and disrupt these Asp-Tyr pairs. Thisstructural data will greatly advance the development of MmpL3 inhibitors as newTB drugs.

UBQLN4 Represses Homologous Recombination and Is Overexpressed in Aggressive Tumors.

Olaparib purchased from MCE.

基因組不穩(wěn)定性是人類基因疾病和癌癥的一個(gè)特點(diǎn)。研究人員在常染色體隱性遺傳綜合征家族中發(fā)現(xiàn)了一種有害的 UBQLN4 突變，該綜合征讓人想起基因組不穩(wěn)定疾病。 UBQLN4 的缺乏會(huì)使得基因毒性應(yīng)激的敏感性增加，延遲 DNA 雙鏈斷裂的修復(fù)。蛋白酶體穿梭因子 UBQLN4 被 ATM 磷酸化，并與泛素化 MRE11 相互作用，介導(dǎo)同源重組介導(dǎo)的 DSB 修復(fù)(HRR)的早期步驟。UBQLN4 的缺失導(dǎo)致了 MRE11 在染色質(zhì)中的滯留，促進(jìn)了非生理性的 HRR 過(guò)程在體外和體內(nèi)的活性。相反，UBQLN4 過(guò)表達(dá)抑制 HRR，有利于非同源端連接。此外，我們發(fā)現(xiàn) UBQLN4 在侵襲性腫瘤中過(guò)表達(dá)。與這些 HRR 缺陷的腫瘤一直的是，UBQLN4 過(guò)表達(dá)與 PARP1 抑制劑敏感性有關(guān)。因此，UBQLN4 通過(guò)從受損染色質(zhì)中去除 MRE11 來(lái)抑制 HRR 活性，從而為 PARP1 抑制劑治療 UBQLN4 過(guò)表達(dá)腫瘤提供了一個(gè)治療窗口。

UBQLN4 is phosphorylated by ATM and interacts with ubiquitylated MRE11 to mediate early steps of homologous recombination-mediated DSB repair (HRR). Loss of UBQLN4 leads to chromatin retention of MRE11, promoting non-physiological HRR activityin vitro and in vivo. Conversely, UBQLN4 overexpression represses HRR and favors non-homologous end joining. Moreover, we find UBQLN4 overexpressed in aggressive tumors. UBQLN4 therefore curtails HRR activity through removal of MRE11 from damaged chromatin and thus offers a therapeutic window for PARP1 inhibitor treatment in UBQLN4-overexpressing tumors.

Researchers report that acetylation inhibits cGAS activation and that the enforced acetylation of cGAS by aspirin robustly suppresses self-DNA-induced autoimmunity. Importantly, we show that aspirin can directly acetylate cGAS and efficiently inhibitcGAS-mediated immune responses. Finally, we demonstrate that aspirin can effectively suppress self-DNA-induced autoimmunity in Aicardi-Goutières syndrome(AGS) patient cells and in an AGS mouse model. Thus, our study reveals that acetylation contributes to cGAS activity regulation.
 

Listeria hijackshost mitophagy through a novel mitophagy receptor to evade killing.

BAPTA-AM purchased from MCE.

細(xì)胞利用線粒體自噬清除受損或不需要的線粒體來(lái)維持體內(nèi)平衡。在此，研究人員發(fā)現(xiàn)胞內(nèi)的細(xì)菌病原體單核增生李斯特菌利用宿主的線粒體自噬逃避殺傷。發(fā)現(xiàn) L.單核細(xì)胞基因通過(guò)毒性因子 LLO 誘導(dǎo)巨噬細(xì)胞的線粒體自噬。發(fā)現(xiàn) NLRX1 是唯一具有線粒體靶向序列的類節(jié)點(diǎn)受體(NLR)家族成員，它包含一個(gè) LC3 相互作用區(qū)域(LIR)，并通過(guò) LIR 與 LC3 直接相關(guān)。NLRX1 及其 LIR 基序?qū)?L.單核細(xì)胞產(chǎn)生的線粒體自噬是必不可少的。單核細(xì)胞誘導(dǎo)產(chǎn)生線粒體自噬。NLRX1 的缺乏和一種線粒體自噬抑制劑的使用都增加了活性氧種類的線粒體產(chǎn)量，從而抑制了單核細(xì)胞基因 L.的存活。從機(jī)制地層面上講，L.單核細(xì)胞基因和 LLO 誘導(dǎo) NLRX1 寡聚化，促進(jìn)其LIR 基序與 LC3 結(jié)合，誘導(dǎo)線粒體自噬。我們的研究發(fā)現(xiàn) NLRX1 是一種新的線粒體自噬受體，并發(fā)現(xiàn)了一種以前未被重視的策略，即病原體利用該策略劫持宿主細(xì)胞的穩(wěn)態(tài)系統(tǒng)以維持其生存。

Researchers report that the intracellular bacterial pathogen Listeria monocytogenes exploits hostmitophagy to evade killing. We found that L. monocytogenes induced mitophagy in macrophages through the virulence factor listeriolysin O (LLO). We discovered that NLRX1, the only Nod-like receptor (NLR) family member with a mitochondrialtargeting sequence, contains an LC3-interacting region (LIR) and directly associated with LC3 through the LIR. NLRX1 and its LIR motif were essential for L. monocytogenes-induced mitophagy. Mechanistically, L. monocytogenes and LLO induced oligomerization of NLRX1 to promote binding of its LIR motif to LC3 forinduction of mitophagy. Our study identifies NLRX1 as a novel mitophagy receptor and discovers a previously unappreciated strategy used by pathogens to hijack a host cell homeostasis system for their survival.