Nuclear Envelope Permeability Barrier as a Fast-Response Intracellular Mechanostat.

Victor Shahin,Ivan Liashkovich,Gonzalo Rosso,Ivan U Kouzel

doi:10.1002/advs.201900709

Abstract

The nuclear envelope is an undisputed component of the intracellular mechanotransduction cascades which collect, process, and respond to mechanical stimuli from the environment. At the same time, the nuclear envelope performs the function of a selective barrier between the nuclear and cytoplasmic compartments. Although the mechanosensing and the barrier functions of the nuclear envelope have both been subjects of intense research, a possible reciprocal relationship between them is only beginning to emerge. In this report, the role of the nucleocytoplasmic permeability barrier is evaluated in nuclear mechanics. Using a combination of atomic force and confocal microscopy, the functional state of the nucleocytoplasmic permeability barrier and the nuclear mechanics is monitored. By modulating the stringency of the barrier and simulating the active transport imbalance across the nuclear envelope, the decisive impact of these parameters on nuclear mechanics is demonstrated. It is concluded that the nucleocytoplasmic barrier is the second essential component of the intracellular mechanostat function performed by the nuclear envelope.

Highlights

The nuclear envelope is an undisputed component of the intracellular mechanotransduction cascades which collect, process, and respond to mechanical stimuli from the environment
Modeling the operation of the nuclear envelope according to the principles of an ultrafiltration system (Figure 1a) is based on understanding several key parameters
We investigated the functional interplay between the mechanical and the transport/barrier function of the nuclear envelope using a combination of a confocal laser scanning and atomic force microscopy

Summary

Experimental Strategy for Validation of the Nuclear Ultrafiltration Model

Modeling the operation of the nuclear envelope according to the principles of an ultrafiltration system (Figure 1a) is based on understanding several key parameters. Once the permeability barrier is compromised, the larger volume change induced by the external mechanical load together with a lower gradient of colloid-osmotic pressure across the nuclear envelope may result in a slower rate of recovery from the deformation This may have a significant impact when the nucleus is exposed to a sequence of brief mechanical stimuli following each other in a rapid succession (Figure 4a). In the case of the nucleus, the upper limit of such a mechanical equilibrium between the external mechanical load and the colloid-osmotic pressure across the nuclear envelope will be defined by the level of lamin A/C expression Forces beyond this limit will result in a mechanical rupture of the nuclear envelope.[33] Under physiological conditions well below this limit, the functional state of the nuclecytoplasmic permeability barrier plays a prominent role in defining both the static elasticity of the nucleus and the mechanical response to high frequency intermittent mechanical loads. Relegation of this function of the pressurized container to the nucleus through forming a dense network of lamins has equipped metazoan cell with a greater degree of flexibility in interacting with and adapting to their environment

Conclusions

Experimental Section

Conflict of Interest