Reactome | CYLD:SPATA2:LUBAC binds TNFR1 signaling complex

CYLD:SPATA2:LUBAC binds TNFR1 signaling complex

Stable Identifier

R-HSA-9796379

Type

Reaction [binding]

Species

Homo sapiens

Compartment

plasma membrane, cytosol

Synonyms

TNF:TNFR1:TRADD:TRAF2:K63polyUb-RIPK1:BIRC2,3 recruits LUBAC:SPATA2:CYLD

ReviewStatus

5/5

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CYLD:SPATA2:LUBAC binds TNFR1 signaling complex

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The N-terminal methionine-linked ubiquitin (Met1-Ub) chains, or linear Ub chains, are conjugated to target proteins by the linear ubiquitin chain assembly complex (LUBAC) composed of HOIL-1L, HOIP, and SHARPIN (Kirisako T et al. 2006; Walczak H et al. 2012). LUBAC and linear polyubiquitination has been implicated in the regulation of innate immunity and cell death (Tokunaga F et al. 2011; Gerlach B et al. 2011). LUBAC activity is regulated by deubiquitinases (DUBs) such as OTULIN and CYLD, which hydrolyze Ub chains to reverse the modification of target proteins (Takiuchi T et al. 2014). OTULIN and CYLD associate with HOIP, the catalytic subunit of LUBAC, to cleave Ub chains in a linkage-specific fashion. OTULIN exclusively hydrolyzes Met1-Ub, while CYLD disassembles both Met1-Ub and Lys63-Ub (Fiil BK et al. 2013; Harhaj EW and Dixit VM 2012; Hrdinka M et al. 2016; Sato Y 2022). The CYLD interaction with LUBAC is facilitated by spermatogenesis-associated protein 2 (SPATA2) (Elliott PR et al. 2016; Kupka S et al. 2016; Schlicher L et al. 2016; Wagner SA et al. 2016). Genome-wide siRNA screen identified SPATA2 as a gene involved in mediating necroptosis (Hitomi J et al. 2008). Structural and biochemical studies revealed that the N-terminal PNGase/UBA or UBX (PUB) domain of SPATA2 interacts with the Ub-specific protease (USP) domain of CYLD, whereas the C-terminal PUB-interacting motif (PIM) of SPATA2 binds the PUB domain of HOIP (reviewed in Schlicher L et al. 2017; Elliott PR et al. 2016; Kupka S et al. 2016; Schlicher L et al. 2016). Under steady-state conditions, SPATA2 was found to bridge CYLD and LUBAC forming the trimeric CYLD:SPATA2:LUBAC complex (Wagner SA et al. 2016; Elliott PR et al. 2016; reviewed in Schlicher L et al. 2017). In TNFα-stimulated human and mouse cells, CYLD:SPATA2:LUBAC is rapidly recruited into the TNFR1 signaling complex (Wagner SA et al. 2016; Elliott PR et al. 2016; Kupka S et al. 2016; Schlicher L et al. 2016; Wei R et al. 2017; reviewed in Schlicher L et al. 2017). Knockdown of SPATA2 selectively abolished CYLD interaction with the TNFR1 complex, without abolishing binding of LUBAC components (Wagner SA et al. 2016). Within the TNFR1 signaling complex, SPATA2 promotes the deubiquitinase activity of CYLD resulting in CYLD-mediated removal of Met1- and K63-linked polyubiquitin chains from specific substrates such as RIPK1 (Wei R et al. 2017). SPATA2 deficiency increased the Met1-linked ubiquitination of RIPK1, which resulted in inhibition of RIPK1 kinase activity and RIPK1-mediated cell death in mouse cells (Wei R et al. 2017). SPATA2 deficiency promoted the production of proinflammatory cytokines in TNFα-treated mice in vivo (Wei R et al. 2017). Further, SPATA2 deficiency protected against TNF-induced cell death in human and mouse cells (Wagner SA et al. 2016; Kupka S et al. 2016; Schlicher L et al. 2016; Wei R et al. 2017). These data suggest that SPATA2 regulates inflammatory signaling and cell death program via linking CYLD and LUBAC to limit LUBAC-mediated Met1-Ub.

This Reactome event shows the recruitment of the CYLD:SPATA2:LUBAC complex to the TNFR1 signaling complex.

Literature References

PubMed ID	Title	Journal	Year
27458237	SPATA2 promotes CYLD activity and regulates TNF-induced NF-κB signaling and cell death Maurer, U, Dengjel, J, Brauns-Schubert, P, Dumit, V, Preiss, F, Jakob, C, Wissler, M, Borner, C, Schlicher, L	EMBO Rep	2016
27307491	SPATA2 links CYLD to the TNF-α receptor signaling complex and modulates the receptor signaling outcomes Beli, P, Satpathy, S, Choudhary, C, Wagner, SA	EMBO J	2016
27545878	SPATA2-Mediated Binding of CYLD to HOIP Enables CYLD Recruitment to Signaling Complexes Martino, L, Draber, P, de Miguel, D, Kupka, S, Rittinger, K, Surinova, S, Walczak, H	Cell Rep	2016
27591049	SPATA2 Links CYLD to LUBAC, Activates CYLD, and Controls LUBAC Signaling Elliott, PR, Hrdinka, M, Freund, SM, Fiil, BK, Gyrd-Hansen, M, Christianson, JC, Kessler, BM, McLaughlin, SH, Wagstaff, J, Leske, D, Bagola, K, Komander, D, Volkmar, N	Mol Cell	2016