Lysosomal membrane permeabilization and cathepsin release is a Bax/Bak-dependent, amplifying event of apoptosis in fibroblasts and monocytes

Abstract

Apoptotic stimuli have been shown to trigger lysosomal membrane permeability (LMP), leading to the release of cathepsins, which activate death signaling pathways in the cytosol. However, it is unknown whether this process is an initiating or amplifying event in apoptosis. In this study, we used fibroblasts and monocytes exposed to etoposide, ultraviolet light, FasL or deprived of interleukin-3 (IL-3) to show that LMP and the cytosolic release of cathepsins B, L and D consistently depends on Bax/Bak and components of the apoptosome. Neither Bax nor Bak resided on the lysosomes, indicating that lysosomes were not directly perforated by Bax/Bak but by effectors downstream of the apoptosome. Detailed kinetic analysis of cells lacking cathepsin B or L or treated with the cysteine protease inhibitor, E64d, revealed a delay in these cells in etoposide-and IL-3 deprivation-induced caspase-3 activation and apoptosis induction but not clonogenic survival, indicating that cathepsins amplify rather than initiate apoptosis.

Increased Intracranial Pressure after Diffuse Traumatic Brain Injury Exacerbates Neuronal Somatic Membrane Poration but not Axonal Injury: Evidence for Primary Intracranial Pressure-Induced Neuronal Perturbation

“…In a model of spinal cord injury, cathepsin-B was shown upregulated with higher levels of activity at the epicenter of injury 5 days after injury (Ellis et al, 2005). The redistribution of cathepsin-B from the lysosomal compartment to the cytosol has previously been observed in vitro and after ischemic injury in vivo and is associated with an increase in neuronal death and dysfunction (Hill et al, 1997;Zhang et al, 2009;Kilinc et al, 2010;Oberle et al, 2010;Wang et al, 2011). In vitro cathepsin-B has been shown capable of precipitating cell death under various molecular stimuli within 24 hours when released from lysosomes with compromised membrane integrity in a pathway initiated by cleavage of Bid to form truncated-Bid.…”

Cathepsins are involved in virus-induced cell death in ICP4 and Us3 deletion mutant herpes simplex virus type 1-infected monocytic cells

“…Whether lysosomal membrane permeabilization and cathepsin release into the cytosol are either initiating or amplifying events in d120-induced cell death should be explored. According to a study published recently, lysosomal membrane permeabilization and cathepsin release are caspase 3-and 7-mediated late events and thus are amplifying events for apoptosis (Oberle et al, 2010). Currently, lysosomal membrane permeabilization has been reported to be involved in HIV-1-and parvovirus H1-induced apoptosis (Di Piazza et al, 2007;Laforge et al, 2007).…”

5-Fluorouracil signaling through a calcium–calmodulin-dependent pathway is required for p53 activation and apoptosis in colon carcinoma cells

“…This is well in agreement with a recent report showing that lysosomal membrane permeability and the cytosolic release of cathepsins B, L and D indirectly depend on Bax/Bak and components of the apoptosome. 18 In comparison, BAPTA had a profound effect also on caspase-8 processing, indicating Ca 2 þ as a messenger acting upstream of the caspase cascade. Moreover, although the 5-FU-induced p53 level remained unaffected in the presence of BAPTA, phosphorylation of S15 was reduced considerably, thus positioning the effect of Ca 2 þ in advance of p53 posttranslational modifications (Figure 3a and Supplementary Figure S1).…”