Subversion of Autophagy by Kaposi’s Sarcoma-Associated Herpesvirus Impairs Oncogene-Induced Senescence

Leidal AM, Cyr DP, Hill RJ, Lee PW, McCormick C

Cell Host & Microbe 11:167-180, February 16, 2012

Speaker: Szu-Han Kuo (郭思含)                                  Time:5/16/2012, 1:00-2:00 PM

Commentator: Dr. Chiou-Feng Lin (林秋烽老師)       Location: Room 601

Abstract

Kaposi’s sarcoma-associated herpesvirus (KSHV) belongs to the gamma-herpesvirus, and is the etiologic agent of Kaposi’s sarcoma (KS, a cancer  commonly occurring in AIDS patients). KSHV encodes a viral homolog of cyclin D  (v- cyclin), which triggers host DNA damage responses (DDRs) and the induction  of cellular senescence (normal diploid cells lose the ability to divide), a process commonly known as oncogene-induced senescence (OIS)¹. Another protein encoded  by KSHV is v-FLIP which inhibits autophagy and blocks the host senescence response. The authors found that despite DDRs is characteristic of OIS, KSHV  infected cells display modest levels of autophagy and fail to senesce. These aberrant  responses result from the combined activities of simultaneous expression of both of KSHV v-cyclin and v-FLIP proteins. It has been reported that v-cyclin-induced  senescence is p53-dependent¹. The p53 is the senescence-regulating checkpoint  genes in v-cyclin induced OIS, and is essential for the execution of downstream  autophagy and senescence responses. Rapamycin has been demonstrated to induce autophagy and increase senescence, suggesting that therapeutic targeting of  autophagy may be efficacious in the treatment of KS². Autophagy may represent an  ‘‘Achilles heel’’ in the cellular senescence response, easily inhibited by viral  oncoproteins that have evolved to specifically block its effects. Accumulating  evidencesuggests that autophagy and senescence are the important host defense  mechanism in limiting the effects of oncogenic viruses³.

References

1.  Koopal, S., et al. Viral oncogene-induced DNA damage response is activated in Kaposi sarcoma tumorigenesis. PLoS pathogens 3, 1348-1360 (2007).

2.  Campistol, J.M., et al. Conversion to sirolimus: a successful treatment for posttransplantation Kaposi’s sarcoma. Transplantation 77, 760-762 (2004)

3.  Nikitin, P.A., et al. An ATM/Chk2-mediated DNA damage-responsive signaling pathway suppresses Epstein-Barr virus transformation of primary human B cells. Cell host & microbe 8, 510-522 (2010).