Download Report

凌斌(Pin Ling)老師實驗室
Lab Introduction
主持人：凌斌(Pin Ling)老師
學歷：美國貝勒醫學院微免學博士
國立陽明大學醫技學士
專長學門：免疫學、訊息傳遞、分子生物學
Lab Member
Research Interest
博士班學生:陳冠儒
碩士班學生:呂學奇林宛瑩林峻暘羅尹秋
助理:陳琳方林妙亭
Signaling networks in innate immunity
Innate immunity serves the first line of host defense against pathogen infections and
also bridges to adaptive immunity to build up the full spectrum of immune defenses.
Host recognition of invading pathogens is mediated by Pattern-Recognition Receptors
(PRRs), which can recognize highly conserved Pathogen-Associated Molecular
Patterns (PAMPs) from various microorganisms. Identification of Toll-like receptors
(TLRs) and other PRRs opens a new field to explore innate immunity at the early
stage of pathogen infection. Intracellular innate immune regulators help translate the
PRR signals into the innate immune responses. PRRs sense PAMPs to trigger major
downstream pathways, including NF-kB, MAPK, and/or IRF3/7, thereby leading to the
production of inflammatory cytokines and/or type I interferons (IFNs). Over the past
decades, considerable progress has been made in identification and characterization
of PRRs and innate immune regulators. Much is yet to be explored to appreciate the
operations of the innate immune system and its interactions with the adaptive immune
system.
1. Identification and characterization of a novel innate immune
regulator TAPE
TBK1 (TANK-binding kinase 1) is a noncanonical homolog of IkB kinase (IKK) linking the TLR and RIG-I-like receptor signals to type I IFN
activation. Previously through a proteomic approach, our lab has identified a novel TBK1-interacting protein, termed TAPE (TBK1-Associated
Protein in Endolysosomes). We are thus interested in exploring the potential role of TAPE in regulating the TBK1-mediated IFN pathway.
Expression of TAPE activated three major innate immune signaling pathways, including NF-kB, Erk and TBK1, thereby leading to cytokine
production and the antiviral state. TAPE was shown to reside in the endolysosomal compartments, implying a functional role for TAPE in these
compartments. TAPE interacted with and acted upstream of Trif in the TLR3 and TLR4 signaling pathways. TAPE was also able to complex
with IPS-1 and RIG-I-like receptors (RLRs, including RIG-I and MDA5). Upon RLR stimulation, TAPE acted upstream of IPS-1 to relay the RLR
signals to interferon-beta induction. Knockdown of TAPE impaired the TLR3- and RLR-mediated interferon-beta induction and antiviral
responses. Together, our findings indicated that TAPE is an innate immune regulator poised to link the TLR3, TLR4 or RLR signals to antiviral
defenses.
2. A potential role for a TAPE-like protein, termed TAPE-L, in innate immunity
Since our work indicated that TAPE is an innate immune regulator, we then searched the human genome for potential TAPE-related proteins. We
found a TAPE-like protein, termed TAPE-L, with 54.3% amino acid similarity to TAPE. Therefore, We investigate whether TAPE-L plays a role in
regulating innate immune pathways. We found that knockdown of TAPE-L impaired the TLR3, TLR4, and RLR signaling pathways. In addition,
TAPE-L was shown to interact with Trif in presence of TLR3. It was also found that TAPE-L formed a complex with IPS-1 and RIG-I or MDA5. Our
data suggest that TAPE-L is also an innate immune regulator in the TLR3, TLR4, and RLR signaling pathways. Ongoing work focuses on
determining the sub-cellular localization of TAPE-L and the molecular mechanisms of how TAPE-L regulates innate immune responses against
pathogen infections.
3. Interactions between the host innate immune system and viruses
To better understand the pathogenesis of viral infection, it is important to elucidate the interactions between viruses and the host immune system.
In collaborations with other faculty here, we are interested in determining how the innate immune system interacts with Influenza A virus (IAV) and
Enterovirus 71 (EV71) at the early stage of infections. Among PRRs, endosomal TLRs (TLR3 and TLR7/8) and RLRs (RIG-I and MDA-5) are
responsible for sensing viral RNA during RNA virus infection. For EV71 project, we aim to determine which of RNA sensors is involved in
recognizing EV71 infection how EV71 may counteract the host innate immune responses. RIG-I, TLR3 and TLR7 are involved in recognition of
IAV infection. Since TAPE family adaptors are shown to involve in the TLR3 and RIG-I pathways, for IAV project we focus on studying the roles of
TAPE family adaptors in innate immune defenses against IAV infection. In addition, the NS1 protein of IAV targets the RIG pathway to IFN
production. Therefore, we are interested in investigating molecular mechanisms by which NS1 and other IAV proteins counteract the innate
immune responses.
Publications
1. Chang, C.-H., Lai, L.-C., Cheng, H.-C., Chen, K.-R., Syue, Y.-Z., Lu, H.-C., Lin, W.-Y., Chen, S.-H., Huang, H.-S., Shiau, A.-L., Lei, H.-Y., Qin, J., and Ling, P. (2010).
TBK1-Associated Protein in Endolysosomes (TAPE) is an innate immune regulator modulating the TLR3 and TLR4 signaling pathways. J. Biol. Chem. (In revision)
2. Ling, P., Lu, T.-J., Yuan, C.-J., Lai, M.-D.(2008). Biosignaling of mammalian Ste20-related kinases. Cell Signal. 20: 1237-1247
3. Li, Z.-H., Li, C.-M., Ling, P., Shen, F.-H., Chen, S.-H., Liu, C.-C., Yu, C.-K., and Chen, S.-H. (2008). Ribavirin Reduces the Mortality of Enterovirus 71-infected 1
Mice by Decreasing Viral Replication. J. Infect. Dis. 197(6):854-857.
4. Giri, DK., Ali-Seyed, M., Li, L.-Y., Lee, D.-F., Ling, P., Bartholomeusz, G., Wang, S.-C. and Hung, M.-C. (2005). Endosomal transport of ErbB-2: a mechanism for
nuclear entry of cell surface receptor. Mol. Cell. Biol. 25: 11005-11018.
5. Ling, P., and Tan, T.-H. (2002). Signal transduction by HPK1, a mammalian STE20-related serine/threonine protein kinase (Review). Recent Res. Devel. Mol. Cell.
Biol. 3: 297-315.
6. Ling, P., Meyer, C. F., Redmond L. P., Shui, J.-W., Davis, B., Rich, R. R., Hu, M. C.-T., Wange, R. L., and Tan, T.-H. (2001). Involvement of hematopoietic progenitor
kinase 1 (HPK1) in T-cell receptor signaling. J. Biol. Chem. 276: 18908-18914.