Caspase-mediated nuclear pore complex trimming in cell differentiation and endoplasmic reticulum stress

Abstract

During programmed cell death, caspases degrade 7 out of ~30 nucleoporins (Nups) to irreversibly demolish the nuclear pore complex (NPC). However, for poorly understood reasons, caspases are also activated in differentiating cells in a non-apoptotic manner. Here, we describe reversible, caspase-mediated NPC "trimming" during early myogenesis. We find that sublethal levels of caspases selectively proteolyze 4 peripheral Nups, Nup358, Nup214, Nup153, and Tpr, resulting in the transient block of nuclear export pathways. Several nuclear export signal (NES)-containing focal adhesion proteins concomitantly accumulate in the nucleus where they function as transcription cofactors. We show that one such protein, FAK (focal adhesion kinase), drives a global reconfiguration of MBD2 (methyl CpG binding domain protein 2)-mediated genome regulation. We also observe caspase-mediated NPC trimming during neurogenesis and endoplasmic reticulum (ER) stress. Our results illustrate that the NPC can be proteolytically regulated in response to non-apoptotic cues, and call for a reassessment of the death-centric view of caspases.

The Nuclear Pore Complex: Birth, Life, and Death of a Cellular Behemoth

“…First, modulation of the NTR complement at the NPC can regulate the available transport pathways. Such effects have been reported for mRNA and protein export [211][212][213][214][215]. For example, the budding yeast mRNA export factor Sac3 is released from the nuclear basket in newly budded daughter cells, which leads to an inhibition of mRNA export [214], and similarly, bulk mRNA export is inhibited by the release of the cytoplasmic mRNA export factor Dbp5 from the NPC during glucose starvation [212].…”

“…Peripheral and membrane NUPs in particular exhibit significant variability in expression levels across different cell types [65,[207][208][209]. However, more acute modifications of NPCs, e.g., during stress response signaling [210][211][212][213], differentiation [211] or in relation to the cell cycle [202,214,215], require regulatory mechanisms that can act on shorter time scales and are potentially restricted to subsets of NPCs. Two such mechanisms have been described in the generation of NPC variants: PTMs and proteolytic cleavage.…”

“…Acute changes to NPC composition can also be induced by proteolytic cleavage. In the early stages of apoptosis, several NUPs are targeted by caspases [211,[220][221][222][223][224], leading to the removal of the cytoplasmic filaments and the nuclear basket [225] and to the loss of NPC barrier function [226]. Intriguingly, caspase-dependent degradation of a set of peripheral NUPs was recently reported to also occur during cellular differentiation and ER stress [211].…”

Macrophage differentiation requires DNA damage caused by Caspase-Activated DNase

“…Other mechanisms might also help survival after caspase activation 102,103 . For example, in vitro studies of caspase-mediated skeletal muscle cell differentiation reported that nuclear pore complex trimming alters the intracellular environment 104 , and CAD-mediated DNA damage is repaired by base excision repair protein XRCC1, resulting in gene expression changes 41,105 . Differential accessibility of transient CAD for DNA fragmentations helps cells survive due to their chromatin architecture 106,107 .…”