Alternative splicing regulates PACC1 function and promotes acidosis-induced cytotoxicity

Area of Science:

• Molecular Biology
• Cell Biology
• Neuroscience

Background:

• The proton-activated chloride channel 1 (PACC1), also known as TMEM2006, plays a role in acid-induced cell death.
• Its tissue distribution, cellular localization, and the specific functions of its different isoforms are not fully understood.

Purpose of the Study:

• To investigate the tissue distribution and cellular expression of PACC1.
• To characterize the functional differences between PACC1 splice variants.

Main Methods:

• RNAscope in situ hybridization and RT-PCR were used to map PACC1 expression and splicing in human tissues.
• Quantitative cell-type-specific co-detection and functional assays in reconstituted cells were employed to assess isoform properties.

Main Results:

• PACC1 is widely expressed, with high uniform expression in the brain, found in both neurons and astrocytes, predominantly in astrocytes.
• Two major splice variants, PACC1-V1 and PACC1-V2, show distinct tissue and developmental expression.
• PACC1-V2 localizes to endosomes, preventing hyperacidification, while PACC1-V1 localizes to the plasma membrane, enhancing acid-induced cell death.

Conclusions:

• Alternative splicing of PACC1 influences its channel trafficking and function.
• Distinct PACC1 isoforms likely have specialized roles in cellular development and acid stress responses, especially within the nervous system.