Multifaceted roles of TAX1BP1 in autophagy

Abstract

TAX1BP1 is a selective macroautophagy/autophagy receptor that plays a central role in host defense to pathogens and in regulating the innate immune system. TAX1BP1 facilitates the xenophagic clearance of pathogenic bacteria such as Salmonella typhimurium and Mycobacterium tuberculosis and regulates TLR3 (toll-like receptor 3)-TLR4 and DDX58/RIG-I-like receptor (RLR) signaling by targeting TICAM1 and MAVS for autophagic degradation respectively. In addition to these canonical autophagy receptor functions, TAX1BP1 can also exert multiple accessory functions that influence the biogenesis and maturation of autophagosomes. In this review, we will discuss and integrate recent findings related to the autophagy function of TAX1BP1 and highlight outstanding questions regarding its functions in autophagy and regulation of innate immunity and host defense.Abbreviations: ATG: autophagy related; CALCOCO: calcium binding and coiled-coil domain; CC: coiled-coil; CHUK/IKKα: conserved helix-loop-helix ubiquitous kinase; CLIR: noncanonical LC3-interacting region; GABARAP: gamma-aminobutyric acid receptor associated protein; HTLV-1: human T-lymphotropic virus 1; IFN: interferon; IL1B/IL1β: interleukin 1 beta; LIR: LC3-interacting region; LPS: lipopolysaccharide; MAP1LC3/LC3: microtubule-associated protein 1 light chain 3; MAPK/JNK: mitogen-activated protein kinase; mATG8: mammalian Atg8 homolog; MAVS: mitochondrial antiviral signaling protein; MEF: mouse embryonic fibroblast; MTB: Mycobacterium tuberculosis; MYD88: myeloid differentiation primary response gene 88; NBR1: NBR1, autophagy cargo receptor; NFKB/NF-κB: nuclear factor of kappa light polypeptide gene enhancer in B cells; OPTN: optineurin; Poly(I:C): polyinosinic:polycytidylic acid; PTM: post-translational modification; RB1CC1: RB1-inducible coiled-coil 1; RIPK: receptor (TNFRSF)-interacting serine-threonine kinase; RLR: DDX58/RIG-I-like receptor; RSV: respiratory syncytia virus; SKICH: SKIP carboxyl homology; SLR: SQSTM1 like receptor; SQSTM1: sequestosome 1; TAX1BP1: Tax1 (human T cell leukemia virus type I) binding protein 1; TBK1: TANK-binding kinase 1; TICAM1: toll-like receptor adaptor molecule 1; TLR: toll-like receptor; TNF: tumor necrosis factor; TNFAIP3: TNF alpha induced protein 3; TNFR: tumor necrosis factor receptor; TOM1: target of myb1 trafficking protein; TRAF: TNF receptor-associated factor; TRIM32: tripartite motif-containing 32; UBD: ubiquitin binding domain; ZF: zinc finger.

Keywords: Aggrephagy; TAX1BP1; autophagy; host defense; innate immune signaling; xenophagy.

Figure 1.

Domain structure of SLRs. TAX1BP1 contains a SKICH domain (containing the CLIR) and the LIR. The central region contains three coiled-coil domains which play a role in self oligomerization. Designated in red are phosphorylation sites critical for TAX1BP1 to suppress the activation of inflammatory signaling pathways [13].The C-terminal region contains two zinc finger domains of which ZF2 functions as a Ub binding domain. Each ZF domain contains a PPXY motif which are required for regulation of anti-inflammatory and anti-viral signaling [13,14]. In addition to TAX1BP1, the SLRs SQSTM1, OPTN, CALCOCO2 and NBR1 all share domains important for LC3 interaction, oligomerization and ubiquitin binding. Created with BioRender.

Figure 2.

TAX1BP1 adaptor functions in mATG8-dependent and mATG8-independent autophagy. (A) TAX1BP1 binds to substrates with its ZF domains and tethers these substrates to the phagophore with its LIR domain. LGALS8 positive phagosomes are sequestered in a similar manner; however, TAX1BP1 binds LGALS8 via its LGALS8-binding domain, residing between the CC3 and UBD [33]. (B) TAX1BP1 has two well documented accessory functions. It promotes mATG8-independent autophagy by binding NBR1 with the C-terminal half of its CC2 domain (termed the “N-Domain”) and simultaneuously recruits RB1CC1 through its SKICH domain [73]. TAX1BP1 also aids in amphisome formation by binding extra-phagosomal LC3 with its LIR domain and the MYO6 tail with its UBD [4,74,85]. Created with BioRender.

Figure 3.

TAX1BP1 inhibits RLR and TLR3-TLR4 signaling pathways. (A) During RNA virus infection, cytosolic RLRs activate MAVS which then forms functional aggregates. MAVS aggregate formation triggers the induction of type I IFN, proinflammatory cytokines, and apoptosis [15,48–50]. TAX1BP1 targets MAVS for degradation to inhibit RLR signaling. (B) TLR3 and TLR4 serve as innate immune receptors for dsRNA and LPS respectively, which then recruit the adaptor protein, TICAM1. TICAM1 subsequently induces type I IFN and proinflammatory cytokines, or recruits other RHIM-domain containing proteins (RIPK1, RIPK3) to initiate cell death by necroptosis [51–59]. TAX1BP1 targets TICAM1 for degradation to inhibit TLR3-TLR4 signaling. Created with BioRender.