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Principal Investigator: Anthony R Fehr
Organization: UNIVERSITY OF KANSAS LAWRENCE
Fiscal Year: 2024
Award: $359,480
Funding agency: National Institute of General Medical Sciences
PROJECT SUMMARY
ADP-ribosylation is an important post-translational modification that directly influences several
biological processes including cancer, allergy, and infectious disease. ADP-ribose can be added to proteins as
one or more consecutive units by ADP-ribosyltransferases, also termed PARPs, resulting in mono- or poly-
ADP-ribosylation (mAR or pAR). Most mARylating PARPs are upregulated by interferon (IFN) upon virus
infection and several are predicted to have antiviral functions. In addition, several viral families, including the
Coronaviridae and Togaviridae, encode for macrodomain proteins that have mono-ADP-ribosyl hydrolase
(ARH) activity. This activity allows these viruses the ability to specifically counteract the effects of mAR, further
implicating mAR in the mammalian antiviral response. Despite these findings, there are only a few known
examples where mAR is known to inhibit virus replication. This is largely due to the lack of cell culture models
of virus infections where the mAR status of a cell can be specifically controlled, such as models using mutant
viruses or PARP knockout cells that have significant phenotypes. Importantly, the PI has established a virus
infection system using a model coronavirus, Murine Hepatitis Virus (MHV), where virus lacking ARH activity is
i) significantly impaired in virus replication and ii) independently induces a robust IFN response. These
phenotypes are reversed by PARP inhibitors, establishing mAR as a key factor driving this anti-viral response.
The investigator’s long-term goal is to determine mechanistically how mAR inhibits virus replication and
enhances the innate immune response following virus infection. This gap in knowledge will be resolved by
answering the following questions: 1) How does mAR inhibit MHV infection? Does it inhibit the entry, RNA
replication, protein translation, assembly, or release of MHV? 2) What step(s) of the IFN induction pathway is
enhanced by mAR, and does mAR also affect the IFN response in bats, which are known to harbor many
highly pathogenic viruses? 3) What proteins are modified by PARPs following virus infection and which
substrates are relevant for specific phenotypes? The rationale for this research is that it will enhance our
understanding of mAR, including its ability to modulate protein function and will uncover novel cellular proteins
or processes that mediate virus replication. The work is innovative because: i) it will bridge a significant
knowledge gap between ADP-ribose biology, the innate immune response, and virus replication; ii) it utilizes
unique models of infection utilizing both mutant viruses and PARP knockout cells; and iii) will be the first to
address the role of mAR in bats. Finally, these projects are significant and relevant to the NIGMS mission
because they will provide a thorough understanding of how mAR impacts the anti-viral response that could lay
the foundation for advances in the treatment of virus infections or other human diseases impacted by mAR.
Terms: <ADP Ribose><ADP Ribose Transferases><ADP ribosylation><ADP-Ribosyltransferase><ADPRTs><ART Transferases><ARTases><Address><Adenosine 5'-(trihydrogen diphosphate), P'-5-ester with D-ribose><Adenosine 5'-Diphosphoribose><Adenosine Diphosphate Ribose><Adenosine Diphosphoribose><Affect><Allergy><Anti-viral Response><Anti-viral Therapy><Automobile Driving><Bats><Biological Function><Biological Process><Biology><Cancers><Cell Body><Cell Culture Techniques><Cells><Chiroptera><Communicable Diseases><Coronaviridae><Coronavirus><Family><Foundations><Goals><Hydrolase><Hydrolase Family Gene><Hydrolase Gene><Hypersensitivity><IFN><Immune response><Immunological response><Immunomodulation><Impairment><Infection><Infectious Disease Pathway><Infectious Diseases><Infectious Disorder><Innate Immune Response><Interferons><Investigators><Knock-out><Knockout><Knowledge><Malignant Neoplasms><Malignant Tumor><Mediating><Mission><Modeling><Mouse Hepatitis Coronavirus><Mouse Hepatitis Virus><Murine Gastroenteritis Virus><Murine hepatitis virus><NIGMS><National Institute of General Medical Sciences><PARP Inhibitor><PARP-1 inhibitor><PARPi><Pathway interactions><Phenotype><Phosphorylation><Poly(ADP-ribose) Polymerase Inhibitor><Poly(ADP-ribose) polymerase 1 inhibitor><Post-Translational Modification Protein/Amino Acid Biochemistry><Post-Translational Modifications><Post-Translational Protein Modification><Post-Translational Protein Processing><Posttranslational Modifications><Posttranslational Protein Processing><Process><Protein Modification><Protein Phosphorylation><Proteins><RNA replication><Research><Research Personnel><Researchers><Role><System><Togaviridae><Togaviruses><Translations><Viral><Viral Activity><Viral Diseases><Viral Function><Viral Physiology><Viral hepatitis><Virus><Virus Diseases><Virus Replication><Work><cell culture><cell cultures><corona virus><driving><hepatitis virus infection><host response><human disease><immune modulation><immune regulation><immune system response><immunologic reactivity control><immunomodulatory><immunoregulation><immunoregulatory><immunoresponse><innate immune mechanisms><innovate><innovation><innovative><malignancy><murine hepatitis coronavirus><mutant><neoplasm/cancer><novel><pathogenic virus><pathway><protein function><response><social role><translation><viral infection><viral infectious disease treatment><viral multiplication><viral pathogen><viral replication><virus infection><virus multiplication><virus pathogen><virus-induced disease>