Multifaceted Roles of the E3 Ubiquitin Ligase RING Finger Protein 115 in Immunity and Diseases

Abstract

Ubiquitination is a post-translational modification that plays essential roles in various physiological and pathological processes. Protein ubiquitination depends on E3 ubiquitin ligases that catalyze the conjugation of ubiquitin molecules on lysine residues of targeted substrates. RING finger protein 115 (RNF115), also known as breast cancer associated gene 2 (BCA2) and Rab7-interacting RING finger protein (Rabring7), has been identified as a highly expressed protein in breast cancer cells and tissues. Later, it has been demonstrated that RNF115 catalyzes ubiquitination of a series of proteins to modulate a number of signaling pathways, and thereby regulates viral infections, autoimmunity, cell proliferation and death and tumorigenesis. In this review, we introduce the identification, expression and activity regulation of RNF115, summarize the substrates and functions of RNF115 in different pathways, and discuss the roles of RNF115 as a biomarker or therapeutic target in diseases.

Keywords: DNA damage repair; RNF115; antiviral immunity; autoimmunity; cancers.

Figure 1

Conserved domains of RNF115. The BZF domain (yellow) binds ubiquitin and is the site of RNF115 auto-ubiquitination (ubiquitinated lysine residues are shown in red). The 14-3-3 binding domain (green) is site of RNF115-14-3-3 interaction (AKT phosphorylation residues are shown in red). The RING H2 domain (blue) is the site of RNF115 autoubiquitination. The E3 ligase activity residues were shown in red.

Figure 2

The signaling pathways regulated by RNF115 in innate immunity. In steady state, RNF115 constitutively interacts with and catalyzes K48-linked ubiquitination of MAVS, leading to the proteasomal degradation of homeostatic MAVS. Upon infection with RNA viruses, RIG-I–MAVS interaction led to RNF115 dissociation from MAVS, thereby initiating downstream signal transduction. Moreover, RNF115 functions as a restriction factor for HIV-1 infection. Firstly, RNF115 interacts with BST2 to promote the newly synthesized HIV-1 particles on the plasma membrane for lysosomal degradation. Secondly, RNF115 directly catalyzes ubiquitination of HIV-1 Gag, leading to its lysosomal degradation independently on BST2. Thirdly, RNF115 targets IκBα for SUMOylation, inhibiting HIV-1-induced NF-κB activation and HIV-1 transcription. In addition, The 14-3-3 chaperones bind to AKT1-phosphorylated RNF115 and facilitate RNF115 localizing at the ER. RNF115 interacts with and induces K63-linked ubiquitination of MITA at ER during infection of DNA viruses, promoting aggregation of MITA and the production of type I IFNs and proinflammatory cytokines. RNF115 also interacts with TLRs and buds off the ER onto the coat protein complex II vesicles. RNF115 catalyzes K11-linked ubiquitination of RAB1A to inhibit the extraction of RAB1A by GDI1. In addition, RNF115 inhibits the post-Golgi trafficking of TLR2, TLR4, and TLR9 by catalyzing K11-linked ubiquitination on RAB13. Consequently, the trafficking of TLR4 from the Golgi apparatus to cell surface and the trafficking of TLR9 to cell surface en route to endolysosomes were inhibited. Finally, RNF115 also inhibits phagosome maturation during S. aureus infection.