Multifaceted roles of TAX1BP1 in autophagy

Figures & data

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.

Table 1. TAX1BP1-interacting proteins and functions in autophagy.

Protein	TAX1BP1 domain interaction	Function	Source
Canonical SLR Function
Atg8-family proteins	LIR	TAX1BP1 interacts with mATG8 family member proteins to anchor its substrates to the phagophore.	[4,16,31]
LC3C	CLIR	TAX1BP1 interacts with the mATG8 family member LC3C to entrap ubiquitinated Salmonella within the autophagosome.	[4,16,31]
LGALS8/galectin 8	LGALS8 Binding Domain / CC3-UBD	TAX1BP1 interacts with LGALS8 to anchor MTB-positive phagosomes to the phagophore.	[33]
TRIM32	Unknown	TAX1BP1 interacts with TRIM32 to degrade TICAM1 following TLR3/TLR4 stimulation.	[51]
Ubiquitinated protein aggregates	ZF2	TAX1BP1 interacts with and clears ubiquitinated protein aggregates through autophagy.	[7]
Polyubiquitinated Mitochondria	ZF2*	TAX1BP1 facilitates PRKN-mediated mitophagy through an interaction with polyubiquitin chains on the outer membrane of damaged mitochondria.	[69]
Accessory Function
NBR1	CC2/”N-Domain”	TAX1BP1 interacts with NBR1 in mATG8-independent autophagy.	[73]
RB1CC1	SKICH	TAX1BP1 interacts with RB1CC1 in mATG8-independent autophagy. It is thought that this interaction promotes phagophore engulfment in the absence of mATG8 family members.	[73]
MYO6 (myosin VI)	ZF2	TAX1BP1 interacts with MYO6 to influence amphisome formation by bridging autophagosomes to TOM1-positive endosomes.	[74,75]
*Presumed interaction domain

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.

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