A model for coordinating nuclear mechanics and membrane remodeling to support nuclear integrity

Abstract

A polymer network of intranuclear lamin filaments underlies the nuclear envelope and provides mechanical stability to the nucleus in metazoans. Recent work demonstrates that the expression of A-type lamins scales positively with the stiffness of the cellular environment, thereby coupling nuclear and extracellular mechanics. Using the spectrin-actin network at the erythrocyte plasma membrane as a model, we contemplate how the relative stiffness of the nuclear scaffold impinges on the growing number of interphase-specific nuclear envelope remodeling events, including recently discovered, nuclear envelope-specialized quality control mechanisms. We suggest that a stiffer lamina impedes these remodeling events, necessitating local lamina remodeling and/or concomitant scaling of the efficacy of membrane-remodeling machineries that act at the nuclear envelope.

Nuclear morphologies: their diversity and functional relevance

“…Supporting this, based on modelling of the spectrin-actin network in the erythrocyte plasma membrane, King and Lusk (2016) proposed that a stiffened nuclear lamina hinders chromatin remodelling, which we have seen accompanies cell type differentiation. Furthermore, embryonic stem cells have a nuclear stiffness that depends upon the level of compression experienced by the cell.…”

“…They act as linkers within the nuclear envelope proteins, and to the cytoskeleton or the nucleoskeleton (Rajgor and Shanahan 2013). The role of spectrins outside the nucleus has been well studied; they help to provide the flexibility and elasticity that smooth muscle nuclei and other organelles require during contraction (Wang and Volk 2015; King and Lusk 2016). They also appear to have a role in the development of nuclear shape in sperm; in falciform sperm, such as from rats, spectrin has been found to be associated with the apical hook (Dvořáková et al 2005), suggesting a contribution to the development of the sperm shape, as well as a functional contribution to capacitation and the acrosome reaction (Bastián et al 2010).…”

Chm7 and Heh1 collaborate to link nuclear pore complex quality control with nuclear envelope sealing

“…It is well established that the nuclear envelope (NE) in multicellular eukaryotes undergoes a dramatic breakdown and reformation during cell division (Wandke & Kutay, 2013), while emerging work suggests that the two membranes of the NE undergo extensive remodeling during interphase as well (Hatch & Hetzer, 2014;King & Lusk, 2016). Classic examples are the insertion of massive protein assemblies like nuclear pore complexes (NPCs) (Rothballer & Kutay, 2013) and the yeast centrosome (spindle pole body; SPB) into the NE, but now extend to the nuclear egress of "mega" ribonucleoprotein particles through a vesicular intermediate in the NE lumen/perinuclear space (Speese et al, 2012;Jokhi et al, 2013) and the degradative clearance of nuclear/NE contents by autophagy pathways that act specifically at the NE (Roberts et al, 2003;Dou et al, 2015;Mochida et al, 2015).…”

Fantastic nuclear envelope herniations and where to find them

“…As is with the case of NE herniations caused by cell migration through constrictions, these herniations are chromatin-filled and occur at sites of lamina discontinuity[107,109,110]. It remains enigmatic how mechanical force is translated into the formation of a herniation but it is clear that this process is directly impacted by extracellular cues some of which trigger elaborate feedback mechanisms that modulate the output of both nuclear and cytosolic cytoskeletons[3,111–113]. It is likely that a combination of misregulation of these feedback mechanisms with defects in the mechanical networks themselves (e.g.…”