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Characterizing the role of BPIFB proteins during positive strand RNA virus infection

Evans, Azia S (2020) Characterizing the role of BPIFB proteins during positive strand RNA virus infection. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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The lifecycle of positive strand RNA viruses occurs in close association to host intracellular membranes as a mechanism to isolate viral replication from cellular restriction factors and innate immune detection. Distinct virus families rely on different membrane sources, each employing unique strategies to manipulate host membranes for their own advantage. One major source of these membranes is the endoplasmic reticulum (ER), which functions at the center of many cellular processes, including secretory pathway and autophagy vesicle trafficking. We have identified Bactericidal/permeability-increasing protein (BPI) fold-containing family B3 (BPIFB3) as a host endoplasmic reticulum (ER) localized protein that differentially controls the replication of two distinct virus families, enteroviruses and flaviviruses, through a non-canonical autophagy pathway. BPIFB3 belongs to the BPIFB protein family which have predicted lipid binding and transfer abilities. This family of proteins has been largely uncharacterized, and their intracellular function has remained to be elucidated. Here we expand on our previous work and address the cellular function of BPIFB3 in two parts. First, we focus on the effects of BPIFB3 induced autophagy on the replication of two flaviviruses, dengue virus (DENV) and Zika virus (ZIKV), and determine that the reticulophagy mediated turnover of ER membranes during BPIFB3 depletion inhibits DENV and ZIKV replication. Second, we identify two unique BPIFB3 binding partners, ADP Ribosylation Factor GTPase Activating Protein 1 (ARFGAP1) and Transmembrane emp24 domain-containing protein 9 (TMED9), that are required for the induction of BPIFB3si mediated non-canonical autophagy. Lastly, we expand on the work presented here in the context of what is known about non-canonical autophagy regulation and present a novel model for BPIFB3 function. We further discuss the downstream effects of BPIFB3 depletion on autophagy regulation and positive strand RNA virus replication. This work defines BPIFB3 as a novel regulator of flavivirus replication and provides meaningful insights into the mechanisms of non-canonical autophagy regulation and their impact on positive strand RNA virus replication.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Evans, Azia Saziaevans@pitt.eduase210000-0002-8309-5222
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Thesis AdvisorCoyne, Carolyn
Committee ChairBomberger, Jennifer
Committee MemberDermody, Terence
Committee MemberLakdawala, Seema
Committee MemberBrodsky, Jeffery
Date: 10 November 2020
Date Type: Publication
Defense Date: 28 August 2020
Approval Date: 10 November 2020
Submission Date: 16 September 2020
Access Restriction: 1 year -- Restrict access to University of Pittsburgh for a period of 1 year.
Number of Pages: 116
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Microbiology and Immunology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: BPIFB proteins, non-canonical autophagy, reticulophagy, virus-host interactions
Date Deposited: 11 Nov 2020 03:10
Last Modified: 10 Nov 2021 06:15


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