CASP6

CASP6 Full Name

Caspase 6

CASP6 Introduction

Caspases are an evolutionarily extremely conserved family of cysteine proteases which function as "molecular switches" during the life of a cell, and are best known for their central role in apoptosis (programmed cell death). Caspase-6 is one of the members of this family. Due to its location and role in the apoptotic signaling pathway, it has traditionally been grouped as an "effector caspase", along with caspase-3 and caspase-7. In the canonical apoptotic cascade, the upstream "initiator caspases" (caspase-8 or caspase-9) are activated in response to death signals, and go on to cleave and activate the effector caspases. Once activated, caspase-6 (like all caspases) functions as a highly specific pair of "molecular scissors" that cut its target proteins after aspartic acid residues (Asp), thereby breaking down key structural and functional proteins of the cell, such as lamin A/C, and thus pushing the cell irreversibly towards death.

Figure 1. Activation of CASP6. (Source: Graham RK, et al. 2011)

Caspase-6 is considered a key executor linking upstream pathogenic signals to downstream neuronal damage. In Alzheimer's disease (AD), pathological hallmarks include the abnormal accumulation of Tau protein into neurofibrillary tangles. Strong evidence has shown that caspase-6 activation is an early and crucial event in AD. The activated form of caspase-6 (aCasp-6) is known to cleave the Tau protein at Aspartate 402 (Asp402) or Aspartate 13 (Asp13) in the N-terminal end of the protein. This truncated Tau protein is more toxic and has a higher propensity to aggregate than its full-length counterpart. It more easily forms oligomers and fibrillary tangles, leading to more rapid neuronal death and cognitive impairment. Caspase-6 is also essential for Huntington's disease. Huntington's disease is due to an abnormal CAG trinucleotide repeat expansion in the huntingtin gene. Studies have shown that mutant huntingtin protein is a direct substrate of caspase-6. Cleavage at Aspartate 586 (Asp586) is thought to be a critical step in disease progression. This cleavage event produces a highly toxic N-terminal fragment which aggregates more readily in the nucleus. It also impedes gene transcription, and initiates a host of downstream toxic processes resulting in selective striatal neuronal death.

In the field of cancer, the function of caspase-6 appears more complex and contradictory, exhibiting a "double-edged sword" characteristic. On the one hand, given the role of caspase-6 as an executor of apoptosis, normal expression and function of the protein is essential for the body to cull pre-cancerous cells. In some types of cancer, such as oral cancer, studies have found CASP6 to be downregulated, and low levels of CASP6 expression were dependent on p53 gene mutational status, supporting the hypothesis that caspase-6 could be a tumor suppressor. On the other hand, there is mounting evidence that in some cases activation of caspase-6 at sub-lethal levels may promote malignant tumor progression. For example, research indicates that non-apoptotic caspase activation can enhance cancer cell migration, invasion, and stem cell-like properties.

Alternate Names for CASP6

Apoptosis Related Cysteine Protease; Apoptotic cysteine protease MCH2; Apoptotic protease MCH 2; Apoptotic protease Mch-2; OTTHUMP00000162742; OTTHUMP00000162743; apoptotic protease MCH-2; caspase 6, apoptosis-related cysteine protease; caspase-6; MCH2

• 1. Graham RK, et al. Caspase-6 and neurodegeneration. Trends Neurosci. 2011 Dec;34(12):646-56.
  2. Qi L, et al. Caspase-6 is a key regulator of cross-talk signal way in PANoptosis in cancer. Immunology. 2023 Jul;169(3):245-259.