PACSIN1 regulates the TLR7/9‐mediated type I interferon response in plasmacytoid dendritic cells

Abstract

Plasmacytoid dendritic cells (pDCs) are the professional interferon (IFN)-producing cells of the immune system. pDCs specifically express Toll-like receptor (TLR)7 and TLR9 molecules and produce massive amounts of type I IFN by sensing microbial nucleic acids via TLR7 and TLR9. Here we report that protein kinase C and casein kinase substrate in neurons (PACSIN) 1, is specifically expressed in human and mouse pDCs. Knockdown of PACSIN1 by short hairpin RNA (shRNA) in a human pDC cell line significantly inhibited the type I IFN response of the pDCs to TLR9 ligand. PACSIN1-deficient mice exhibited normal levels of conventional DCs and pDCs, demonstrating that development of pDCs was intact although PACSIN1-deficient pDCs showed reduced levels of IFN-α production in response to both cytosine guanine dinucleotide (CpG)-oligonucleotide (ODN) and virus. In contrast, the production of proinflammatory cytokines in response to those ligands was not affected in PACSIN1-deficient pDCs, suggesting that PACSIN1 represents a pDC-specific adaptor molecule that plays a specific role in the type I IFN signaling cascade.

Recognition of pathogen-associated nucleic acids by endosomal nucleic acid-sensing toll-like receptors

“…This complex recruits TAK1 and TAK1-binding proteins 1/2/3 (TAB1/2/3), and is activated by the K63-linked polyubiquitin chain of TRAF6, phosphorylated IKKb, and MAP kinase kinase 6 (MKK6). This phenomenon results in the activation of a classical IKK complex, consisting of IKK1/a, IKK2/b, and IKK3/g (also called NF-kB essential modulator, NEMO), which leads to IkB degradation and thereby contributes to the activation of NF-kB and MAPK signaling pathways to induce secretion of inflammatory cytokines [1][2][3][7][8][9][151][152][153].…”

“…MyD88 is a specific adaptor molecule containing a TIR domain in its C-terminal region and a dead domain in its N terminal region. Upon stimulation, TLRs 7, 8, and 9 interact with the TIR domain of MyD88 to recruit signaling molecules IL-1 receptorassociated kinases 4/1/2 (IRAK4/1/2) and interact with TRAF3/6, Ubc13, and Uev1A, forming a signaling complex [1][2][3][7][8][9]151]. This complex recruits TAK1 and TAK1-binding proteins 1/2/3 (TAB1/2/3), and is activated by the K63-linked polyubiquitin chain of TRAF6, phosphorylated IKKb, and MAP kinase kinase 6 (MKK6).…”

“…1). In this case, TRIF directly interacts with the TIR domain of TLR3 to recruit a set of adaptor molecules, including TNF receptor-associated factor 6 (TRAF6), TNF receptorassociated death domain, Pellino1, and receptor interacting protein 1 (RIP1) for the activation of TAK1 [1,2,7,8,151], which in turn leads to the activation of IRF3, mitogenactivated protein kinases (MAPKs), and NF-kB. On the other hand, interactions of TLR3-TRIF with TRAF3, nonclassical NAK-associated protein 1 (NAP1), TBK1, and IKKi (also called IKK1) lead to the formation of a complex and the activation of IRF3, which then translocates to the nucleus to induce the expression of IFN-b and IFN-inducible genes [1][2][3]7,8,151].…”

“…However, recognition of 'self'-nucleic acids by the nucleic acid-sensing TLRs contributes to the pathology associated with several autoimmune or autoinflammatory diseases under certain pathological conditions. In this review, we discuss the recent progress in studies of pathogen-associated nucleic acid recognition and signaling pathways within endosomal compartments, and the individual functions of TLRs 3,7,8,9, and 13 in innate immunity. In addition, we discuss the compartmentalization, intracellular trafficking, proteolytic cleavage, autophagy, and regulatory programs of these TLRs in innate immunity.…”

“…Distribution, Subcellular Localization and Regulation of TLRs 3,7,8,9,and 13 Distribution of TLRs 3,7,8,9, and 13 The expression of TLRs 3,7,8,9, and 13 is distinct in different cell types of human and murine origins. TLR3 is observed in the human myeloid DCs (mDCs), macrophages, natural killer cells, and B cells [6,16].…”