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

Area of Science:

• Cell Biology
• Molecular Biology
• Biochemistry

Background:

• Caspases are known to degrade nucleoporins during apoptosis, leading to nuclear pore complex (NPC) disassembly.
• The role of caspases in cell differentiation, despite their activation, remains poorly understood.

Purpose of the Study:

• To investigate the function of sublethal caspase activation during cell differentiation.
• To elucidate the impact of caspase-mediated nucleoporin (Nup) proteolysis on nuclear pore complex (NPC) function and nuclear transport.

Main Methods:

• Myogenesis and neurogenesis models were used to study caspase activation.
• Mass spectrometry was employed for unbiased identification of Nups and proteins affected by NPC trimming.
• Analysis of nuclear export defects and protein accumulation within the nucleus.

Main Results:

• Sublethal caspase activation during myogenesis transiently degrades specific nucleoporins (Nups), including peripheral and transmembrane Nups.
• 'Trimmed' NPCs exhibit nuclear export defects, leading to the accumulation of various proteins in the nucleus.
• NPC trimming by non-apoptotic caspases was also observed in neurogenesis and endoplasmic reticulum stress.

Conclusions:

• Caspases can reversibly modulate nuclear transport activity at sublethal levels.
• NPC trimming by caspases functions as a mechanism for cell differentiation and adaptation.
• This reversible modulation of nuclear transport highlights a novel role for caspases beyond apoptosis.