Immunity in humans and all animals: feedback loops (Introduction)

by David Turell , Wednesday, October 26, 2016, 20:51 (2738 days ago) @ David Turell

This article demonstrates a feedback loop in controls of interferon, a major generalized antibody that offers excellent protection without being specific as many antibodies are:

http://journals.plos.org/plosbiology/article?id=10.1371/journal.pbio.2000117

Author summary:

"For more than a quarter century, we have known that STAT1 and STAT2 are essential for the classic host immune defense system against viral infections known as the type 1 interferon response. While STAT1 has since been assigned multiple additional roles, STAT2 is thought to function exclusively as the principal partner of STAT1 in the type 1 interferon system. However, patients and animals that are deficient in STAT2 show a surprisingly varied and sometimes subtle phenotype not fully accounted for by the known functions of this protein. Our investigations reveal an entirely novel facet of STAT2 action, namely as an innate inhibitor of STAT1 in its multiple biological roles. We identify the molecular mechanism of STAT1 inhibition and generate a novel biological tool with which we can dissociate STAT2’s activating and inhibitory effects on STAT1. We use this tool to show that STAT2 has major roles beyond antiviral protection, for example, in regulating cell proliferation and immune cell functions, as well as in killing intracellular parasites. These findings considerably expand our knowledge of STAT2 biology and necessitate a reassessment of regulatory mechanisms central to innate immunity and the therapeutic use of interferons.

***

"The identification of STAT2 as another perpetual STAT1 inhibitor, in addition to SUMO, underscores the importance of constitutive signal-dampening mechanisms in STAT1 biology to avoid disease associated with STAT1 hyperactivity. However, STAT2 does not target the activation of STAT1, but the subsequent step, its nuclear import. This is a new cytokine modulation mechanism for a STAT protein, but one reminiscent of viral IFN evasion strategies, e.g., by Ebola virus VP24 protein. The results moreover provide an alternative interpretation for the functioning of the STAT1ẞ splice variant, which in lacking a transactivation domain is generally considered a STAT1 antagonist with an unclear biological role. In light of the findings reported here, it can be seen as a STAT2 quencher–through its N domain–and hence rather as a promoter of cytokines that signal via STAT1. Finally, the constitutive interactions between STAT2 and STAT1 are exceedingly tight, yet highly vulnerable to mutation of either STAT1 or STAT2 , suggesting strong evolutionary pressure in favor of heterodimerization. Counterintuitively, heterodimerization was dispensable for the assembly and the functioning of canonical ISGF3. It thus appears that the binding of STAT2 to STAT1 exists not because it supports the cytokine inducible activities of STAT2, but because it attenuates those of STAT1. (my bold)

Comment: Over reaction of immune mechanisms can cause autoimmune diseases, rheumatoid arthritis as one example. Interferons can be very powerful in their effects. The article shows a control mechanism in place. Note my bold above. The entire body is filled with this sort of controls for precise results in body functions, which are not fixed but constantly responding to changing situations.