Multiplexing information flow through dynamic signalling systems

Abstract

We provide experimental evidence suggesting that the NF-κB transcription factor can multiplex information about changes in multiple signals in the sense that the NF-κB target genes response can identify which of these signals have changed. In view of this, we consider how a signalling system can act as an information hub by multiplexing multiple signals. We formally define multiplexing, mathematically characterise which systems can multiplex and how well they can do it. We believe this may resolve the apparent paradox of how a system like NF-κB that regulates cell fate and inflammatory signalling in response to diverse stimuli can appear to have the low information carrying capacity suggested by recent studies on scalar signals. In carrying out our study, we introduce new methods for the analysis of large, nonlinear stochastic dynamic models, and develop computational algorithms that facilitate the calculation of fundamental constructs of information theory such as Kullback-Leibler divergences and sensitivity matrices, and link these methods to new theory about multiplexing information. We show that many current models such as those of the NF-κB system cannot multiplex effectively and provide models that overcome this limitation using post-transcriptional modifications.

Proofreading Is Too Noisy For Effective Ligand Discrimination

“…Our results naturally lead to a question: if KPR commonly does not enhance the resolution of a sensory system, what other purpose might it serve in receptor systems like the TCR? One possibility is that KPR might enable multiplexing of signals in receptor mixtures by producing multiple statistically independent outputs from different proofreading states (53, 76, 77). These outputs can be used to infer the presence of multiple ligands in a mixture (53), convey information about ligand concentration or other environmental conditions in addition to ligand identity (77), or perform other complex signaling processing tasks (78).…”

“…One possibility is that KPR might enable multiplexing of signals in receptor mixtures by producing multiple statistically independent outputs from different proofreading states (53, 76, 77). These outputs can be used to infer the presence of multiple ligands in a mixture (53), convey information about ligand concentration or other environmental conditions in addition to ligand identity (77), or perform other complex signaling processing tasks (78). Mounting experimental evidence indicates that the TCR (as a case study for KPR) may indeed produce multiple intracellular second messengers which may enable T cells to detect antigen quantity alongside antigen quality (78–82).…”

“…Our results naturally lead to a question: if KPR commonly does not enhance the resolution of a sensory system, what other purpose might it serve in receptor systems like the TCR? One possibility is that KPR might enable multiplexing of signals in receptor mixtures by producing multiple statistically independent outputs from different proofreading states (53,76,77).…”

Multiplexing and its upper bound in biological sensory receptors

“…In information science, a sensor or information channel that can simultaneously pass on multiple channels of information is called multiplexing or muxing [21]. It has been recently pointed out by Minas et al that NF-κB regulatory networks are capable of performing muxing [22]. Moreover, the concept of observing and even controlling high-dimensional non-linear dynamical systems by low dimension (reduced) observables have been constructed in the 1970s for deterministic non-linear systems [23][24][25].…”

“…(−2.61 ± 0.01) × 10 −1 (19) λ µ,β (−1.89 ± 0.01) × 10 −1(20)Similarly given β, the sensor can simultaneously sense both × 10 −3(22) and given µ, the sensor simultaneously senses both β and v x 95 ± 0.01) × 10 −1…”