Abstract
Like most plasma membrane proteins, type I interferon (IFN) receptor (IFNAR) traffics from the outer surface to the inner compartments of the cell. Long considered as a passive means to simply control subunits availability at the plasma membrane, an array of new evidence establishes IFNAR endocytosis as an active contributor to the regulation of signal transduction triggered by IFN binding to IFNAR. During its complex journey initiated at the plasma membrane, the internalized IFNAR complex, i.e. IFNAR1 and IFNAR2 subunits, will experience post-translational modifications and recruit specific effectors. These finely tuned interactions will determine not only IFNAR subunits destiny (lysosomal degradation vs. plasma membrane recycling) but also the control of IFN-induced signal transduction. Finally, the IFNAR system perfectly illustrates the paradigm of the crosstalk between membrane trafficking and intracellular signaling. Investigating the complexity of IFN receptor intracellular routes is therefore necessary to reveal new insight into the role of IFNAR membrane dynamics in type I IFNs signaling selectivity and biological activity.
Highlights
The IFNAR signaling pathway plays a central role in the defenses of the organism by supporting one of the major anti-viral and anti-proliferative cellular responses
This study put into question the classical dogma stating that hepatocyte growth factor-regulated tyrosine kinase substrate (Hrs) and signaltransducing adaptor molecule (STAM) are always constitutively associated on the endosomal membrane to form the endosomal sorting complex required for transport (ESCRT)-0 complex
The endosome is a crucial sorting station where a concerted choreography between Hrs/STAM and retromer complexes sequentially control the initiation and the termination of IFNinduced Janus tyrosine Kinases (JAK)/signal transducers and activators of transcription (STAT) signaling. Since their discovery more than 60 years ago, numerous studies have tried to unravel the mechanisms underlying the signaling activity of IFNs and their cognate IFNAR receptor. These studies have mainly focused on the initiation of JAK/STAT signaling at the plasma membrane in a linear manner
Summary
The IFNAR signaling pathway plays a central role in the defenses of the organism by supporting one of the major anti-viral and anti-proliferative cellular responses. It is accepted that endocytosis holds an essential role in the activity of a large number of receptors including receptor tyrosine kinases (RTK) and G protein-coupled receptors (GPCR) families [reviewed in [2, 3]]. IFNAR Trafficking and Signaling clathrin-dependent or clathrin-independent means. This simplistic binary classification did not resist further investigations and today several molecular machineries including caveolin, endophilinA2, RhoA, Cdc, Arf, flotillin or endophilinA3/galectin selectively control distinct endocytic pathways [7,8,9]. Despite the existence of specific molecular machineries, these different endocytic pathways share the common property that is to modulate the cell surface density of a multitude of receptors, a process that is essential for the cell homeostasis and the transduction of receptor signaling [10, 11]. We will describe recent studies on IFNAR journey from the cell surface to the different endosomal compartments and how it is connected with the regulation of signaling outputs
Sign-in/Register to view highlights & summary 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.
