SPATA2 links CYLD to LUBAC

Stable Identifier
R-HSA-9796691
Type
Reaction [binding]
Species
Homo sapiens
Compartment
plasma membrane, cytosol
ReviewStatus
5/5
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SPATA2 links CYLD to LUBAC
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Genome-wide siRNA screening identified spermatogenesis-associated protein 2 (SPATA2 ) as a gene involved in mediating necroptosis (Hitomi J et al. 2008). Under steady-state conditions, SPATA2 was shown to interact with deubiquitinating enzyme CYLD and HOIP, the catalytic subunit of the linear ubiquitin chain assembly complex (LUBAC) (Wagner SA et al. 2016; Elliott PR et al. 2016; reviewed in Schlicher L et al. 2017). Structural and biochemical studies revealed that the N-terminal PNGase/UBA or UBX (PUB) domain of SPATA2 interacts with the 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). 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.

The Reactome event shows the formation of the CYLD:SPATA2:LUBAC complex. The stoichiometry of the trimeric CYLD:SPATA2:LUBAC complex is shown as 2:2:2 (Elliott PR et al. 2016).

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
Participants
Input
Output
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Authored
Shamovsky, V  (2022-08-09)
Reviewed
Tu, H  (2022-08-10)
Created
Shamovsky, V  (2022-08-12)
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