Disruption of ceramide synthesis by CerS2 down-regulation leads to autophagy and the unfolded protein response

By Stefka D. Spassieva, T. Mullen, D. Townsend, LM Obeid. 2009

127 citations recorded by the source corpus.

Ceramide metabolism has come under recent scrutiny because of its role in cellular stress responses. CerS2 (ceramide synthase 2) is one of the six mammalian isoforms of ceramide synthase and is responsible for the synthesis of VLC (very-long-chain) ceramides, e.g. C24, C24:1. To study the role of CerS2 in ceramide metabolism and cellular homoeostasis, we down-regulated CerS2 using siRNA (small interfering RNA) and examined several aspects of sphingolipid metabolism and cell stress responses. CerS2 down-regulation had a broad effect on ceramide homoeostasis, not just on VLC ceramides. Surprisingly, CerS2 down-regulation resulted in significantly increased LC (long-chain) ceramides, e.g. C14, C16, and our results suggested that the increase was due to a ceramide synthase-independent mechanism. CerS2-down-regulation-induced LC ceramide accumulation resulted in growth arrest which was not accompanied by apoptotic cell death. Instead, cells remained viable, showing induction of autophagy and activation of PERK [PKR (double-stranded-RNA-dependent protein kinase)-like endoplasmic reticulum kinase] and IRE1 (inositol-requiring 1) pathways [the latter indicating activation of the UPR (unfolded protein response)].

Subfields: Cell Biology, Epidemiology, Molecular Biology

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In Cell Biology

1. Michal Levy
2. J. Bielawski
3. A. Futerman

In Molecular Biology

1. Michal Levy
2. A. Futerman
3. J. Bielawski
4. B. Ogretmen
5. Yusuf A. Hannun

Citations in the corpus

• Mammalian Ceramide Synthases (2010, background): “CerS2 knockdown resulted in the induction of autophagy and activation of the unfolded protein response (UPR) (54).”
• Impairment of ceramide synthesis causes a novel progressive myoclonus epilepsy (2014, background): “Previous studies showed that downregulation of specific ceramide synthases in vitro leads to apoptosis (CerS6) or autophagy (CerS2) through the activation of ER stress response pathways.(12,13) ER is required for the appropriate synthesis and folding of proteins.”