Hepatitis C virus (HCV) infection is closely tied to the lipid metabolism of liver cells. Here, we identify the triglyceride-synthesizing enzyme DGAT1 as an important host factor for HCV infection; DGAT1 interacts with the viral nucleocapsid core and is required for the trafficking of core to lipid droplets. Inhibition of DGAT1 activity or RNAi-mediated knockdown severely impairs infectious virion production, implicating DGAT1 as a new target for antiviral therapy.Over 160 million individuals are infected with HCV, and in ~80% of cases, infection persists and can lead to severe liver disease. No vaccine is available, and current treatments are not effective against the strains most prevalent in the US and Europe. After the virus enters liver cells, a viral polyprotein is translated at the endoplasmic reticulum (ER) from a single positive-stranded RNA genome and processed into structural and nonstructural proteins 1 . Nonstructural proteins autonomously replicate viral RNA, which together with structural proteins, the nucleocapsid core and E1 and E2 envelope proteins, is packaged into progeny virions. Both RNA replication and infectious particle assembly are thought to occur at ER membranes. However, recent reports showed a critical involvement of lipid droplets Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms * To whom correspondence should be addressed: Melanie Ott, MD, PhD, Gladstone Institute of Virology and Immunology, 1650 Owens Street, San Francisco, CA 94158, Tel: (415) Fax: (415) Competing financial interestsThe authors declare no competing financial interests. LDs form when triglycerides and cholesterol esters accumulate between the bilayer of the ER membrane and are surrounded by a phospholipid monolayer and associated proteins 8 . DGAT1 and DGAT2 enzymes catalyze the final step in triglyceride biosynthesis and are critical in LD biogenesis 9 . Both enzymes are ER-resident, and upon uptake of fatty acids, DGAT2, but not DGAT1, localizes to LDs 9 . Both enzymes have similar activities in vitro; however, DGAT1 has broader substrate specificity 9 , and only DGAT2 is essential in vivo in vivo 10,11 . HHS Public AccessTo determine if DGAT enzymes influence the HCV life cycle, shRNAs directed against DGAT1 or DGAT2 were introduced into HCV-permissive hepatoma cells [12][13][14] . Transduced cultures were inoculated with low concentrations of infectious HCV expressing eGFP as a marker for infection (eGFP-Jc1), and viral spread was monitored by flow cytometry (Fig. 1a). Spreading infection was suppressed by 65-90% with two DGAT1 shRNAs (day 9 post infection). Expression of shRNA-resistant DGAT1 rescued the suppressive effect of the DGAT1 knockdown on viral infection ( Supplementary Fig. S1). No change was seen with DGAT2 shRNA pointing to a unique role of DGAT1 in HCV infection. Knockdown of DGAT expre...

Damage-associated molecular patterns (DAMPs) are released in response to cell death and stress, and are potent triggers of sterile inflammation. Recent evidence suggests that DAMPs may also have a key role in the development of cancer as well as in the host response to cytotoxic anti-tumor therapy. As such, DAMPs may exert protective functions by alerting the immune system to the presence of dying tumor cells, thereby triggering immunogenic tumor cell death. On the other hand, cell death and release of DAMPs may also trigger chronic inflammation and thereby promote the development or progression of tumors. Here, we will review the contribution of candidate DAMPs and their receptors and discuss the evidence for DAMPs as tumor-promoting and anti-tumor effectors as well as unsolved questions such as DAMP release from non-tumor cells as well as the existence of tumor-specific DAMPs.

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