Abstract
Human Immunodeficiency Virus-1 (HIV-1) is known to induce the expression of SOCS3 which is a negative feed-back regulator of inflammatory responses. Here, we demonstrate that reactivation of latent HIV-1 leads to degradation of SOCS3 at early time points. Interestingly, SOCS3 degradation following transfection of HIV-1 RNA as well as polyIC in THP-1 cells further confirmed the role of viral RNA signaling in SOCS3 biology. Degradation of SOCS3 contributes toward viral RNA induced inflammatory responses. NF-κB signaling is also induced upon HIV-1 infection which leads to the production of pro-inflammatory cytokines to control the viral spread. Further investigations revealed that SOCS3 inhibits the expression and activity of p65 by interacting with it and inducing its ubiquitin-dependent proteasomal degradation. SH2 domain was critical for SOCS3-p65 interaction and p65 degradation. We also found that expression of SOCS3 promotes HIV-1 replication. Thus, HIV-1 downregulates SOCS3 in early phase of infection to promote inflammatory responses for large production of activated cells which are suitable for viral spread and induces SOCS3 later on to limit inflammatory responses and ensure viral survival.
Highlights
Cytokines are secreted from the cells in response to diverse range of stimuli including microbial infections and inflammation
It was observed that TNFα induced Human Immunodeficiency Virus-1 (HIV-1) reactivation in U1 cells led to rapid degradation of SOCS3 upto 6 h of TNFα treatment followed by an increase in expression of SOCS3 at later time points (Figure 1A upper panel)
TNFα treatment of control U937 cells led to induction of SOCS3 (Figure 1A lower panel) thereby suggesting that early events in reactivation of HIV-1 leads to the specific degradation of SOCS3
Summary
Cytokines are secreted from the cells in response to diverse range of stimuli including microbial infections and inflammation. They bind to their respective receptors leading to the induction of downstream signaling cascade. Nuclear factor kappa B (NF-κB) activation leads to the induction of cytokines and inflammatory responses This pathway is evolutionary conserved and is essential for development and maintenance of immune-homeostasis (Hayden and Ghosh, 2011). This is tightly regulated by IkB kinase (IKK) complexes. It has been shown that several proteins like ODLIM2 and SOCS1 can induce p65 ubiquitination and proteasomal degradation leading to termination of NF-κB signaling (Ryo et al, 2003; Saccani et al, 2004; Tanaka et al, 2007; Strebovsky et al, 2011)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
