Stress and the Single Cell: Apoptosis-Mediating Pathway May Lead to New Therapeutic Strategies

Mammalian cell biology is filled with dramatic stories of cellular “altruism” in which individual cells, irreparably damaged by stress, contribute to the greater health of an organism by initiating apoptosis, or programmed cell death.  But what would drive a single-celled organism to initiate the apoptotic process?  In a study recently published in Science Signaling, BINA faculty member Prof. Shulamit Michaeli identified a molecular pathway that controls apoptosis in parasitic protozoa called trypanosomes.  Moreover, she explains why this discovery may someday lead to a new, bio-based form of chemotherapy.

“Trypanosomes have an unusual form of gene transcription,” Michaeli says. “Entire chromosomes are transcribed into long RNAs, which are then cut apart into individual coding sequences that represent each gene.  This is mediated by a ‘trans-splicing’ process that must occur before messenger RNA can translate the genetic material into a protein. If this trans-splicing is blocked, protein synthesis is shut down, and the cell will die.

Along with members of her lab and colleagues at the University of Connecticut, Michaeli recently discovered a novel stress-induced mechanism that blocks the trans-splicing of trypanosome mRNA. “When there is consistent stress to the ER – the network of tubes that transfer chemical compounds in and out of the cell – we found that trypanosomes undergo a process we call SLS, or spliced leader silencing,” she says. “This abolishes the trans-splicing as well as mRNA production.”

Michaeli achieved her “proof of concept” by silencing a trypanosome kinase that, under normal circumstances, sits on the ER surface, but in times of stress moves to the nucleus, where it triggers cellular suicide. As a result of kinase silencing, the cell death that would normally be the fate of this stressed trypanosome did not occur.

Now, Michaeli’s challenge will be finding a drug compound capable of “switching on” this kinase, so that that cellular apoptosis can be activated at will. According to Michaeli, this approach has therapeutic potential, because the genes associated with ER stress are preserved from yeast to man.

This article was originally published in the BINA Newsletter No. 3 - March 2015