Abstract
Receptor interacting protein kinase 3 (RIP3 or RIPK3), the critical executor of cell programmed necrosis, plays essential roles in maintaining immune responses and appropriate tissue homeostasis. Although the E3 ligases CHIP and PELI1 are reported to promote RIP3 degradation, however, how post-translational modification regulates RIP3 activity and stability is poorly understood. Here, we identify the tripartite motif protein TRIM25 as a negative regulator of RIP3-dependent necrosis. TRIM25 directly interacts with RIP3 through its SPRY domain and mediates the K48-linked polyubiquitination of RIP3 on residue K501. The RING domain of TRIM25 facilitates the polyubiquitination chain on RIP3, thereby promoting proteasomal degradation of RIP3. Also, TRIM25 deficiency inhibited the ubiquitination of RIP3, thus promoting TNF-induced cell necrosis. Our current finding reveals the regulating mechanism of polyubiquitination on RIP3, which might be a potential therapeutic target for the intervention of RIP3-dependent necrosis-related diseases.
Highlights
Cell programmed necrosis acts as an alternative way of apoptosis when apoptosis is inhibited, functioning in defense of pathogen-infected cells and damaged cells during inflammatory stimulations [1, 2]
The results showed that the tripartite motif protein TRIM25 had a high sPSM score and could be the potential interacting protein of RIP3
To confirm the interaction between TRIM25 and RIP3, FLAG-tagged RIP3 was transfected into HEK239T and HeLa cells; it showed that RIP3 co-immunoprecipitated with endogenous TRIM25 (Fig. 1a)
Summary
Cell programmed necrosis ( called necroptosis) acts as an alternative way of apoptosis when apoptosis is inhibited, functioning in defense of pathogen-infected cells and damaged cells during inflammatory stimulations [1, 2]. Receptor interacting protein kinase 3 (RIP3 or RIPK3) and its family protein RIP1 (or RIPK1) forms a large complex called necrosome, which is required in the TNF induced cell necroptosis [5,6,7]. RIP3 is a switch molecule for the interconversion between apoptosis and programmed cell necrosis [6]. Phosphorylated RIP3 binds with and phosphorylates its downstream protein mixed lineage kinase domain-like (MLKL), promoting MLKL oligomerization, eventually triggering necrotic cell death [5, 11,12,13,14]
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