Hijacking ER protein quality control machinery during virus infection

A. Polyomavirus 

     Polyomaviruses (PyVs) are responsible for causing devastating human diseases, especially in immunocompromised patients. Prominent human PyVs include the BK virus that induces hemorrhagic cystitis and nephropathy, JC virus that causes progressive multifocal leukoencephalopathy, and the Merkel cell PyV that triggers Merkel cell carcinoma. SV40 is the archetype PyV, possessing structural and genetic similarities to human PyVs, as well as sharing the same infection pathway as its human counterparts. Not surprisingly, studies on SV40 entry have illuminated the cellular basis of human PyV infection.

     To infect cells, SV40 undergoes receptor-mediated endocytosis, and is transported to endosomal compartments before reaching the endoplasmic reticulum (ER) (Figure 1A). The virus then penetrates the ER membrane to enter the cytosol. From the cytosol, SV40 mobilizes to the nucleus where transcription and replication of the viral genome lead to lytic infection or cellular transformation. How SV40 targets from the endosome to the ER, penetrates the ER membrane to reach the cytosol, as well as transports from the cytosol to the nucleus, are decisive infection steps that remain enigmatic. My lab is investigating these distinct events.

B. Human Papillomavirus

     High-risk human human papillomaviruses (HPVs) cause essentially all cancers of the uterine cervix and are also responsible for other anogenital as well as oropharyngeal cancers. Although prophylactic vaccines against HPV infection are efficacious, cancers associated with HPV infection remain a major disease burden due to the inefficient use of the vaccine and the absence of vaccine benefit in individuals with current HPV infection.

     To enter host cells, HPV is endocytosed, trafficking to the endosome, the Golgi, and then the ER (Figure 1B). HPV then buds from the Golgi/ER compartment. The resulting Golgi/ER-derived vesicle harboring HPV enters the nucleus when the nuclear envelop disassembles during mitosis. In the nucleus, the virus penetrates the vesicular membrane to reach the nucleoplasm where ensuing transcription and replication of the viral genome promote infection. My lab is elucidating different aspects of these HPV entry steps.

C. Zika Virus

     Zika virus (ZIKV) infection has captured significant world-wide attention because of its strong association with congenital malformation during pregnancy (e.g. microcephaly). Insights into the molecular basis of ZIKV infection should therefore expedite efforts in developing effective vaccines and/or drugs against ZIKV infection.

     To infect cells, ZIKV undergoes endocytosis, leading to release of its positive-strand RNA genome (+RNA) into the cytosol (Figure 1C). Subsequent translation and processing of the ZIKV polyprotein on the ER membrane generate both structural and non-structural viral proteins. Some of the non-structural proteins rearrange the ER membrane in order to promote genome replication. Once the replicated genome is assembled with the structural proteins to form the new viral progeny, it exits the cell via secretion to complete the infection cycle. My lab is interested in understanding how the ER protein quality control machinery regulates translation and processing of the ZIKV polyprotein.

Project #1 

Tsai  Lab