Cell-penetrating peptide inhibits retromer-mediated human papillomavirus trafficking during virus entry

Zhang, Pengwei; Moreno, Ruben; Lambert, Paul F.; DiMaio, Daniel

doi:10.1073/pnas.1917748117

Cited by 33 publications

(27 citation statements)

References 34 publications

(48 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…We synthesized a short peptide containing the HPV16 L2 retromer binding sites, the HPV16 or HPV31 L2 CPP, and flanking sequences. When this peptide is added to the culture medium, the peptide enters cells, binds retromer and displaces it from incoming virus, and aborts infection by several pathogenic HPV types [60]. As predicted, inhibitory activity is dependent on both the retromer binding sites and the CPP on the peptide.…”

Section: From Mechanism To Potential Therapeuticsmentioning

confidence: 62%

“…Because retromer evolved to transport cellular, not viral, proteins, compounds that block retromer action are also likely to inhibit transport of cellular cargos. In fact, trafficking of cellular cargos is affected by the peptides discussed above as well as by expression of dominant-negative Rab7 (unpublished and [60]). However, these manipulations do not cause any obvious cellular toxicity under conditions where HPV is strongly inhibited.…”

Section: From Mechanism To Potential Therapeuticsmentioning

confidence: 96%

See 1 more Smart Citation

Papillomaviruses Go Retro

et al. 2020

Self Cite

View full text Add to dashboard Cite

Human papillomaviruses are important pathogens responsible for approximately 5% of cancer as well as other important human diseases, but many aspects of the papillomavirus life cycle are poorly understood. To undergo genome replication, HPV DNA must traffic from the cell surface to the nucleus. Recent findings have revolutionized our understanding of HPV entry, showing that it requires numerous cellular proteins and proceeds via a series of intracellular membrane-bound vesicles that comprise the retrograde transport pathway. This paper reviews the evidence supporting this unique entry mechanism with a focus on the crucial step by which the incoming virus particle is transferred from the endosome into the retrograde pathway. This new understanding provides novel insights into basic cellular biology and suggests novel rational approaches to inhibit HPV infection.Pathogens 2020, 9, 267 2 of 11 with wild-type or mutant capsid proteins, and the convenience of assaying successful infection by measuring reporter gene expression. Nevertheless, authentic papillomaviruses should be used to validate crucial findings obtained with pseudoviruses because there may be important differences between authentic viruses produced in stratified epithelial cells and pseudoviruses produced in a monolayer cell culture [13]. Role of Retrograde Trafficking and Retromer in HPV EntryKnockdown and inhibitor studies have identified numerous cell proteins required for HPV entry and trafficking, including but not limited to furin, kallikrein-8, ADAM17, cyclophilin B, SNX17, SNX27, γ-secretase, VPS4, obscurin-like1, TSG101,TRAPPC8, growth factor receptors, DCT, annexin A2/S100A10, and tetraspanins CD131 and CD63 [8,10,[14][15][16][17][18][19][20][21][22][23][24][25][26][27][28][29]. The proteases furin and kallikrein-8 cleave L2 and L1, respectively. Furin-catalyzed cleavage near the N terminus of L2 occurs at the cell surface, but in the absence of cleavage, intracellular trafficking events are disrupted [30]. ADAM17 appears to assemble an entry platform containing CDC151 and an epidermal growth factor receptor that mediates internalization of HPV [27]. In most cases, however, little is known about the mechanism by which these proteins support HPV infection.To comprehensively identify cellular proteins involved in HPV entry, we conducted a genome-wide siRNA screen. In this screen,~20,000 different siRNA pools were transfected into HeLa cells in a microtiter plate format to repress individual cellular genes, and the ability of an HPV16 pseudovirus to express GFP from the encapsidated reporter plasmid was measured in each well of cells [31]. The results showed that efficient HPV infection requires numerous cellular proteins localized to vesicular compartments such as the trans-Golgi network (TGN) and the endoplasmic reticulum (ER). Subsequent validation studies and more targeted analysis of candidate genes confirmed that these proteins were required for HPV entry [30,31]. Among the required factors identified in these experiments were Rab proteins...

show abstract

Section: From Mechanism To Potential Therapeuticsmentioning

confidence: 62%

Section: From Mechanism To Potential Therapeuticsmentioning

confidence: 96%

Papillomaviruses Go Retro

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…TAT CPP motif was also assessed. Interestingly, the interacting peptide containing retromerbinding motif sequesters retromer from viral entry and inhibits the viral escape from the endosomes, inhibiting infection, the latter was also demonstrated in a mouse infection model [51]. This shows that intracellular virus trafficking is a vulnerability that can be harnessed in therapeutic purposes and retromer binding is a potential antiviral target for the HPV.…”

Section: Pf6 Peptidementioning

confidence: 81%

Status update in the use of cell-penetrating peptides for the delivery of macromolecular therapeutics

Kurrikoff

Vunk

Langel

2020

Expert Opinion on Biological Therapy

View full text Add to dashboard Cite

Introduction: In this review, recent developments and applications with cell-penetrating peptides (CPP) are discussed. CPPs are widely used tools for the delivery of various macromolecular therapeutics, such as proteins and nucleic acids. Areas covered: The current review focuses on recent important advances and reports that demonstrate high clinical and translational potential. Most important clinical developments have occurred with the CPP-drug conjugate approaches that target various protein-protein interactions, and these have been highlighted subsequently. Most of the applications are targeting cancer, but recently, noteworthy advances have taken place in the field of antisense oligonucleotides and muscular dystrophies, lung targeting, and trans-BBB targeting. Expert opinion: Successful applications and clinical development with the drug conjugate approaches are discussed. On the other hand, the reasons of why the nanoparticle approaches are not as far in development are analyzed.

show abstract

“…This study clarifies an important HPV entry event. Upon endosomal arrival, HPV is delivered to the transmembrane protease γ-secretase which promotes insertion of L2 into the endosome membrane and CPP-mediated protrusion of a segment of L2 into the cytosol (Fig 5C, step 2) [24,25,30,31]. The L2 C-terminus in the cytosol in turn recruits cytosolic sorting factors (such as the retromer) which delivers HPV to the Golgi en route for successful infection (Fig 5C, step 3) [32][33][34].…”

Section: Discussionmentioning

confidence: 99%

“…In addition to its well-characterized protease function [28,29], our labs recently discovered that the catalytic subunit of γ-secretase, presenilin-1 (PS1), harbors a novel chaperone activity that promotes insertion of the C-terminus of L2 into the endosome membrane [24]. This insertion event enables this segment of L2 to protrude into the cytosol, a step mediated by a cell-penetrating peptide (CPP) on the C-terminus of the L2 protein [30,31]. Subsequently, host factors such as retromer and SNX17 are recruited to the cytosolic segment of L2, and the virus is guided to the Golgi en route to the nucleus for infection [32][33][34].…”

Section: Introductionmentioning

confidence: 99%

p120 catenin recruits HPV to γ-secretase to promote virus infection

Harwood

Dupzyk

Inoue³

et al. 2020

PLoS Pathog

Self Cite

View full text Add to dashboard Cite

During internalization and trafficking, human papillomavirus (HPV) moves from the cell surface to the endosome where the transmembrane protease γ-secretase promotes insertion of the viral L2 capsid protein into the endosome membrane. Protrusion of L2 through the endosome membrane into the cytosol allows the recruitment of cytosolic host factors that target the virus to the Golgi en route for productive infection. How endosome-localized HPV is delivered to γ-secretase, a decisive infection step, is unclear. Here we demonstrate that cytosolic p120 catenin, likely via an unidentified transmembrane protein, interacts with HPV at early time-points during viral internalization and trafficking. In the endosome, p120 is not required for low pH-dependent disassembly of the HPV L1 capsid protein from the incoming virion. Rather, p120 is required for HPV to interact with γ-secretase-an interaction that ensures the virus is transported along a productive route. Our findings clarify an enigmatic HPV infection step and provide critical insights into HPV infection that may lead to new therapeutic strategies against HPV-induced diseases.

show abstract

Cell-penetrating peptide inhibits retromer-mediated human papillomavirus trafficking during virus entry

Cited by 33 publications

References 34 publications

Papillomaviruses Go Retro

Papillomaviruses Go Retro

Status update in the use of cell-penetrating peptides for the delivery of macromolecular therapeutics

p120 catenin recruits HPV to γ-secretase to promote virus infection

Contact Info

Product

Resources

About