Acid Stress-induced plasma membrane ceramide arises from lysosome-plasma membrane fusion
Plasma membrane ceramide (PMCer) is a recognized cellular signal that regulates stress responses, such as chemotherapy and membrane damage, triggering apoptosis and plasma membrane repair. Acid sphingomyelinase (ASM) has been proposed to generate PMCer by directly hydrolyzing plasma membrane sphingomyelin into ceramide. However, the enzymatic requirements of ASM are difficult to reconcile with…
Acidic stress triggers the generation of plasma membrane ceramide (PMCer) through a novel lysosome-to-plasma membrane pathway. Traditionally, ASM has been thought to produce PMCer by breaking down plasma membrane sphingomyelin into ceramide. However, this process struggles to explain the enzymatic activity in the extracellular environment of the plasma membrane's outer leaflet.
Researchers found that several cellular stress factors, with acidic stress proving most effective, induce PMCer generation. Upon exposing cells to acidic stress, PMCer levels rose in a manner dependent on ASM. However, when ASM was lost or rendered inactive, the response was halted. Surprisingly, secreted ASM, even when tested outside the cell, could not generate PMCer.
The study reveals that acidic stress initiates lysosomal exocytosis, leading to lysosomal fusion with the plasma membrane. This fusion directly transfers ceramide from the lysosome into the plasma membrane, ultimately resulting in PMCer accumulation. The research suggests that PMCer signaling during stress is mediated by the transfer of ceramide from lysosomes to the plasma membrane, fundamentally altering our understanding of this cellular response.
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