Further COPI suppression had little effect on cellular responses in senescent fibroblasts

Further COPI suppression had little effect on cellular responses in senescent fibroblasts

On 24 July, Science Advances published a study of the COPI complex. These seven proteins assemble transport vesicles that carry proteins and lipids between the Golgi apparatus, the endoplasmic reticulum (ER), and endosomes. In cultured human fibroblasts, suppression of each COPI subunit reduced the uptake of extracellular vesicles, but different subunits produced different cellular responses.

The Golgi apparatus packages and sorts cargo, while the ER synthesizes and folds many proteins. COPI returns some cargo from the Golgi to the ER and participates in transport involving endosomes, which serve as intracellular sorting stations. These processes allow the cell to maintain the composition of its compartments and take up extracellular vesicles, small particles that carry proteins and signals from neighboring cells.

The authors suppressed each of the seven COPI genes in proliferating WI-38 fibroblasts. After each intervention, the cells took up less than half as many labeled vesicles. The subunits then separated into two functional groups. Suppression of COPA, COPB1, COPB2, or COPD increased ATF4, a protein that activates the response to ER stress, and altered autophagy, inflammatory signaling, and susceptibility to apoptosis. Suppression of COPE, COPG1, or COPZ1 increased the production of extracellular matrix proteins, which form the fibrous environment that holds cells within tissues. The seven COPI proteins therefore produced two distinct sets of cellular responses.

For the second part of the experiment, the researchers treated WI-38 cells with etoposide for 10 days, inducing senescence, a stable arrest of cell division following damage. In these cells, the Golgi apparatus became enlarged and fragmented into dispersed structures, while vesicle uptake decreased. The authors also observed lower levels of many COPI components in several models of senescence. In etoposide-treated cells, additional COPI suppression had little effect on the measured stress, autophagic, apoptotic, extracellular matrix, and respiratory responses. The authors attribute this result to the weakening of intracellular transport networks during senescence.

In 2023, another study showed that suppression of COPB2 and COPG1 killed senescent IMR90 fibroblasts in models of senescence induced by an oncogene or doxorubicin. The new study used a different cell line and etoposide. In this setting, individual subunits produced different effects, and the senescent cells showed little response to further suppression. Searches for senolytic vulnerabilities therefore need to specify the protein, the cell type, and the method used to induce senescence.