||TAPE-L (TAPE-like) 分子在Toll-like接受體訊號傳遞以及細菌感染的角色
||Roles of TAPE-L adaptor in Toll-like receptor signaling and bacterial infections
||Department of Microbiology & Immunology
Toll-like 接受體 (TLRs) 是PRRs相當代表性的家族，可以辨認許多來自微生物的成分進而誘發先天免疫訊號。許多研究致力於探討TLR如何活化先天性免疫，先前我們實驗室發現了一種先天免疫調控蛋白TAPE (TBK-1 associated protein in endolysosome)。TAPE已被發現可以調控胞內體 TLR3, TLR4, and 細胞質RLR訊號路徑。在人類和小鼠基因組裡，一種 TAPE的同源基因稱作 TAPE-like
(TAPE-L) 已被發現。我們實驗室先前研究指出TAPE-L參與在RLR路徑以抵抗病毒感染，也可聯繫TLR路徑活化NF-κB 以產生發炎細胞激素。延續之前的成果，我有兩個研究方向。第一個方向是研究TAPE-L具體是如何調控TLR- NF-κB 路徑。我的資料顯示TAPE-L在TLR- NF-κB 路徑位於TRAF6和NEMO complex 之間。另一個發現是TAPE-L不會調節 TRAF6的K63泛素化。未來則會探討TAPE-L是否有調控NEMO泛素化的功能。除了NF-κB 活化，我也探討TAPE-L 是否涉及MAPK 分子在TLR路徑的活化.。比較 IκB 分解以活化NF-κB和 ERK-1/2 磷酸化，我發現TAPE-L只調節NF-κB活化；然而TAPE-L卻不會影響ERK-1/2活化。第二個方向是更進一步了解TAPE-L 在TLR路徑以及受細菌感染的功能性角色。利用基因剔除方法研究，我得出的結果是TAPE-L缺乏的小鼠巨噬細胞和纖維母細胞，無論在TLR配體刺激或是革蘭氏陰性細菌，IL-6的活化都有缺陷。此外，TAPE-L不足的小鼠受沙門桿菌感染時，生存狀況變差。除了上述得到的資訊，將來會更詳細探討TAPE-L對於清除體內或細胞內細菌的角色。
Toll-like receptors (TLRs) represent a prototype family of PRRs that can detect a variety of microbial components to trigger innate immune signals. Significant progress has been made in studying TLRs signaling pathways to activate innate immunity. Previous studies in our lab discovered an innate immune regulator , called TAPE (TBK-1 associated protein in endolysosome). TAPE is shown to regulate the endosomal TLR3, TLR4, and cytoplasmic RIG-I-like receptor signaling pathways. A TAPE paralog in the human and mouse genomes was found, called TAPE-like (TAPE-L). Previous findings from our lab showed that TAPE-L was involved in the RLR pathway to defend viral infections, TAPE-L was also found linking surface TLR pathways to NF-κB activation for proinflammatory cytokine production. To continue the effort, my current work focuses two specific aims. My Specific Aim 1 is to study the underlying mechanism of how TAPE-L regulates the TLR- NF-κB pathway. My recent data showed that the position of TAPE-L locates between TRAF6 and NEMO complex in TLR-MyD88 pathways. Another finding is that TAPE-L does not K63 ubiquitination of TRAF6. Future work will determine whether TAPE-L regulates linear ubiquitination of NEMO. In addition to TLR-NF-κB axis, I am also studying on the role of TAPE-L in TLR-MAPK axis. By comparing IκB degradation for NF-κB activation and ERK-1/2 phosphorylation, I found that TAPE-L regulates NF-κB activation in TLR- MyD88 pathways; however, TAPE-L does not influence ERK-1/2 phosphorylation. The Specific Aim 2 is to further study the functional role of TAPE-L in the TLR pathways and bacterial infections by the genetic knockout approach. My preliminary data showed that TAPE-L deficient macrophages and fibroblasts were defective in IL-6 production upon TLR ligand stimulation or Gram-negative bacterial infections. TAPE-L deficient mice showed a poor survival rate during Salmonella infection. In addition to confirming the functional role of TAPE-L in TLR ligand stimulation, future studies will examine bacterial load in TAPE-L-deficient cells and mice.
Pattern recognition receptors
Innate immunity is the first line of defense pathogen infections. Pattern recognition receptors (PRRs) in the innate immune system function to from recognize molecules from pathogens called pathogen-associated molecular patterns (PAMPs). After recognizing PAMPs, PRRs trigger downstream signals to the production of inflammatory cytokines and type I interferon production. Innate immune responses cause vasodilation, vascular permeability, maturation of immune cells like macrophage and dendritic cells (DCs) link innate immunity to adaptive immunity. Several PRR families are identified in the mammalian innate immune system, including Toll-like receptors (TLRs), NOD-like receptors (NLRs), RIG-I-like receptors (RLRs), cell surface C-type lectin receptors (CLRs) and cytosolic DNA receptors like DDX41, STING.
Mammalian TLRs are homolog of Drosophila melanogaster Toll-receptor, so far, 10 human TLRs and 12 mouse TLRs are identified. TLRs consist of an extracellular N-terminal leucine-rich repeats (LRRs), a transmembrance domain and a cytosolic C-terminal Toll/IL-1R homology domain (TIR domain). Cell surface TLRs include TLR1, TLR2, TLR4, TLR5, TLR6, they recognize bacterial ligands like lipoprotein, peptidoglycan, flagellin, LPS. Endosomal TLRs include TLR3, TLR7, TLR8, TLR9, they recognize DNA or RNA from pathogens. Upon recognizing their specific PAMPs, TLRs form homodimers or heterodimers. For example, TLR1 and TLR2 form heterodimer to bind triacyl lipoprotein, TLR4 not only forms homodimer but also needs CD14 and MD2 to bind LPS.
TLRs signaling pathways
TLRs, except TLR3, transduce signal by adaptor protein MyD88 for activation of NF-κB, AP-1, and IRF7. TIR domain of TLRs interacts with TIR domain of MyD88, and MyD88 recruits IRAK family members like IRAK1, IRAK2, IRAK4 to form myddosome complex. Myddosome complex interacts with TRAF6 and activate E3 ligase function of TRAF6. TRAF6 assembles K63 polyubiquitination chains with IRAK complex and other E3 ligase like Pellino 1 and 2. The E2 ligase complex Uev1A:Ubc13 binds K63 ubiquitin chains to activated TRAF6 or downstream molecule NEMO. Activated TRAF6 or free ubiquitin chain recruits TAB1 and TAB2/3 to recruit TAK1 for further signal transduction. Downstream of TAK1, TLR pathways activate NF-κB and AP-1 in different methods. For NF-κB activation, TAK1 recruits and activates IKK complex, IKKγ in IKK complex binds with linear polyubiquitination chains while IKKα and IKKβ are activated by phosphorylation. Then, IκB that binds with NF-κB with be degraded by K48 ubiquitination and NF-κB enters in nuclear for inflammatory cytokine productions. For AP-1 activation, TAK1 transduces signal to MAPKKs, phosphorylated MAPKKs transduce signal to MAPKs, phosphorylated activate AP-1, AP-1 enters in nuclear for inflammatory cytokine productions.
Ubiquitination in TLR-MyD88 pathways
Ubiquitin is a small protein that exists universally in eukaryotic cells. Ubiquitination is the posttranslational modification that ubiquitin is covalently bound to substrate protein with the E1-E2-E3 enzymatic cascade. Ubiquitin includes 7 lysine residues (K6, K11, K27, K29, K33, K48, K63) and 1 methionine residue (M1) for linkage of different polyubiquitin chains. According to the linkage of ubiquitination chains, it regulates substrate proteins to different biological functions. K48 ubiquitination drives substrate protein for degradation, K63 and M1 ubiquitination trigger substrate protein to signal transduction. TRAF6 K63 ubiquitination and NEMO linear ubiquitination are both essential in TLR-MyD88 signaling pathways for NF-κB activation . TRAF6 is activated by oligomerization through CC domain, CC domain also interacts with E2 ligase complex Uev1A:Ubc13. Zn domain of TRAF6 acts as E3 ligase to bind K63 polyubiquitination chains on itself. CC2 and LZ domain of NEMO, or CoZi domain, bind to linear ubiquitin chains. LUBAC complex produces M1-linked linear ubiquitination chains and HOIP of LUBAC acts as E3 ligase that binds linear ubiquitination chains to CoZi domain of NEMO.
The TLR-MyD88 pathways and diseases
TLR-MyD88 pathways play the essential role in defense of bacterial infections, deficiency and mutation of any molecules in TLR pathways impair signal cascades and defect immune responses. Clinical studies showed that patients with deficiencies in TLR pathways cause decreased IL-6 production and pyrogenic bacterial infection like S. aureus, S. pneumoniae, P. aeruginosa. Also, inflammatory diseases like pneumonia, meningitis, sepsis occur.
Roles of TAPE and TAPE-L in innate immunity
TAPE (TBK-1-associated protein in endolysosomes), or called as cc2d1a/Freud-1/Aki, is TBK-1-interacting protein located in endolysosomes. Previous studies in our lab showed that TAPE participates in various of innate immunity pathways. TAPE regulates RLR pathway to IFN-β activation against viral infections, TAPE also links TLR3 pathway to type I interferon production against EV71 infection. TAPE is involved in NOD2 pathway and NLRP3 inflammasome activation against bacterial infections as well. TAPE-L, also known as cc2d1b/Freud-2, is the paralog of TAPE. Studies in our lab found that TAPE-L can activate NF-κB and IFN-β. Also, TAPE-L is involved in RLR pathway and links surface TLR pathways to NF-κB activation. In surface TLR pathways, TAPE-L locates downstream of MyD88. Also, TAPE-L is suggested to regulates inflammatory cytokines production in THP-1 cell and regulates inflammatory response in vivo. Given these data, we further discover mechanistic roles of TAPE-L in surface TLR pathways and whether TAPE-L is essential in inflammatory cytokine production ex vivo and protects hosts against bacterial infections.
First, we focus on mapping the location of TAPE-L in surface TLR pathways. By comparison of NF-κB activation between WT and TAPE-L KO 293T cells with reporter assay, we found that TAPE-L may locate between TRAF6 and IKK complex nearby TARF6 or. Also, results show that TAPE-L does not regulate neither TRAF6 K63 ubiquitination nor MAPKs phosphorylation. We determine that TAPE-L locates between TRAF6 and IKK complex in TLR pathways and does not regulate MAPK activation. In functional roles of TAPE-L ex vivo, both TAPE-L KO MEFs and BMDMs impair inflammatory cytokines production under stimulations and infections. In functional roles of TAPE-L in vivo, data showed that TAPE-L protects survival of mice against bacterial infection; however, TAPE-L does not show significant effect of bacterial clearance in mice. Together, our works further show roles of TAPE-L in regulation of surface TLR pathways signaling under bacterial infections.
Table of contents
Table of contents VIII
List of figures X
1. Introduction 1
1.1 Pattern recognition receptors…………………………………………………....1
1.2 Toll-like receptors 1
1.3 TLR signaling pathways 2
1.4 Ubiquitination in TLR-MyD88 pathways 3
1.5 Role of TAPE in the RIG-I signaling pathway 4
1.6 Roles of TAPE and TAPE-L in innate immunity 5
3. Methods 11
3.1 Bacterial strains 11
3.2 Cell culture and reagents 11
3.3 Generation of HEK293T-TAPE-L CRISPR cells 11
3.4 Isolation and differentiation of bone marrow derived mavrophages 12
3.5 Enzyme-linked immunosorbent assay (ELISA) 12
3.6 Luciferase reporter assay 12
3.7 Co-immunoprecipitation and Western blotting 13
3.8 Animal infection……………………………………………………………….13
3.9 Isolation and differentiation of peritoneal macrophages 14
4. Results 15
4.1 The location of TAPE-L in TLR pathways .. 15
4.2 TAPE-L does not affects TRAF6 ubiquitination in TLR pathways.. 15
4.3 TAPE-L is not required for TLR4 signaling to MAPK activation. 16
4.4 TAPE-L is essential for TLR-mediated inflammatory cytokine production in primary cells under stimulations... 17
4.5 TAPE-L is essential for TLR-mediated inflammatory cytokine production in primary cells under infections. 17
4.6 TAPE-L protects against bacterial infections in vivo. 18
5. Discussion 19
6. References 22
7. Figures and Figure legends 28
8. Appendixes 38
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