Mechanics of a molecular mousetrap—nucleation-limited innate immune signaling

Abstract

Innate immune responses, such as cell death and inflammatory signaling, are typically switch-like in nature. They also involve ''prion-like'' self-templating polymerization of one or more signaling proteins into massive macromolecular assemblies known as signalosomes. Despite the wealth of atomic-resolution structural information on signalosomes, how the constituent polymers nucleate and whether the switch-like nature of that event at the molecular scale relates to the digital nature of innate immune signaling at the cellular scale remains unknown. In this perspective, we review current knowledge of innate immune signalosome assembly, with an emphasis on structural constraints that allow the proteins to accumulate in inactive soluble forms poised for abrupt polymerization. We propose that structurally encoded nucleation barriers to protein polymerization kinetically regulate the corresponding pathways, which allows for extremely sensitive, rapid, and decisive signaling upon pathogen detection. We discuss how nucleation barriers satisfy the rigorous on-demand functions of the innate immune system but also predispose the system to precocious activation that may contribute to progressive age-associated inflammation.

Structural Evolution of TIR-Domain Signalosomes

“…This group comprises the TIR domains that undergo selfassociation to form a scaffold, which facilitates nucleationcontrolled cooperative recruitment of other TIR domaincontaining proteins and signal transduction (employing a SCAF mechanism) (5)(6)(7)25). The group includes TIR domains from mammalian membrane receptors (TLRs and IL-1Rs), as well as those from the cytoplasmic adaptor proteins.…”

“…Compared to a more gradual signal amplification in a classical signaling pathway, SCAF enables a rapid and strong response to minute amounts of stimulus, resembling a switch; it is therefore well suited to innate-immunity and cell-death pathways. An important aspect of regulation involves the nucleation barriers to oligomerization (25). In the case of scaffold TIR-domain assemblies, the effector enzymes correspond to proteins kinases ( I R A K s ) , w h i c h c a n a c t i v a t e t h e m s e l v e s t h r o u g h phosphorylation when brought together.…”

The polyglutamine amyloid nucleus in living cells is a monomer with competing dimensions of order

“…Amyloid phenomena tend to progress toward predetermined fates, such as programmed cell death (Majumdar et al, 2012;Rodríguez Gama et al, 2021), neurodegeneration and aging (Chiti and Dobson, 2017;Huang et al, 2019). The deterministic character of amyloids results from a kinetic barrier to their formation de novo, or "nucleation".…”

“…Amyloids are highly ordered protein aggregates. They are widely associated with aging and neurodegenerative diseases (Chiti and Dobson, 2017; Huang et al, 2019), but also have functional roles in programmed cell death and subcellular compartmentalization (Boke et al, 2016; Hervas et al, 2020; Maji et al, 2009; Majumdar et al, 2012; O’Carroll et al, 2020; Rodríguez Gama et al, 2021; Vogler et al, 2018). These activities derive from an inherent tendency of amyloids to catalyze their own formation, a phenomenon driven by supersaturation resulting from sequence-encoded kinetic barriers to nucleation.…”

“…Once a nucleus does form, additional molecules join with relative ease, depleting the soluble level of the protein and changing its activity throughout the cell or organism. It is for this reason that amyloid phenomena tend to progress toward predetermined fates, such as programmed cell death (Majumdar et al, 2012; Rodríguez Gama et al, 2021), neurodegeneration and aging (Chiti and Dobson, 2017; Huang et al, 2019).…”