Deregulation of caspases forms the basis of many human disease pathogeneses including neurodegeneration and cancer. Although caspases have been extensively studied as initiators, executioners or regulators of cell death mediated by apoptosis, pyroptosis, necroptosis or autophagy, it is clear that caspases actively regulate animal development and the defense of homeostasis through both cell death-dependent and -independent functions.
Caspase activation requires the recruitment of initiator caspases into macromolecular protein complexes that mediate the activation of initiator caspases through proximity-induced dimerization. Activation of initiator caspases depends on the engagement of platforms such as the death-inducing signalling complex, complex-II or ripoptosome for CASPASE-8 (CASP8) or CASP10, the apoptosome for CASP9 and the inflammasome for CASP-1 or -11. These platforms integrate cellular signals and recruit initiator caspases via their death-fold domain, which results in the dimerization of the initiator caspases and formation of an active enzyme.
An important outstanding question is how caspases can be activated to mediate non-apoptotic events without killing the cell. Hypotheses that have been suggested include temporal restriction of activity and amplitude modulation; however, it is not clear how general these modes of regulation are.
By studying how caspases take part in non-apoptotic signalling, authors unexpectedly discovered an evolutionary conserved principle of caspase-mediated control of cellular processes. They find that in both Drosophila and mammals, an unconventional myosin is essential for caspase-mediated regulation of kinases.
The data demonstrate that the Drosophila myosin family member CRINKLED (CK) and its mammalian counterpart Myosin VIIA (MYO7A) act as substrate adaptor for kinases, thereby facilitating caspase-mediated cleavage and localized modulation of kinase activity.
In mammals, this results in inactivation of RIPK1 and suppression of CASP8. In the absence of MYO7A, CASP8-mediated cleavage and inactivation of RIPK1 is less effective. This has important implications, because mutations in MYO7A cause Usher syndrome 1B—an autosomal recessive disorder characterized by bilateral sensorineural hearing loss and blindness due to retinitis pigmentosa.
Despite intense investigation, the mechanisms by which loss of MYO7A results in deafness and blindness are poorly understood. The finding that MYO7A interacts with the initiator CASP8 and dampens its activation may help to explain why patients with mutations in MYO7A suffer progressive loss of sensory neurons.
Given that RIPK1 and CASP8 take part in the defense of homeostasis downstream of many cytokine receptors, it is plausible that inflammatory signals contribute to the onset and progression of retinitis pigmentosa in patients with MYO7A mutations due to aberrant activation of RIPK1-dependent cell death.
Edited
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