Nef stimulates proliferation of glomerular podocytes through activation of Src-dependent Stat3 and MAPK1,2 pathways

He, John Cijiang; Husain, Mohammad; Sunamoto, Masaaki; D’Agati, Vivette D.; Klotman, Mary E.; Iyengar, Ravi; Klotman, Paul E.

doi:10.1172/jci200421004

Cited by 143 publications

(93 citation statements)

References 48 publications

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“…Nef , an accessory gene of HIV-1, mediates podocyte cytoskeletal reorganization during HIVAN [46]. Nef contains a Src homology 3 (SH3)-binding domain, which mediates Src kinase activation, and activation of Stat3 and MAPK1,2 pathways [51]–[53]. The role of nef in mediating podocytopathy, and previous demonstration that MYH9 is down-regulated by HIV-1 in the podocyte [11], indicates that MYH9 down-regulation is likely part of the same nef -mediated signaling cascade that includes RhoA down-regulation.…”

Section: Discussionmentioning

confidence: 99%

Proteomics Analysis of the Non-Muscle Myosin Heavy Chain IIa-Enriched Actin-Myosin Complex Reveals Multiple Functions within the Podocyte

et al. 2014

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MYH9 encodes non-muscle myosin heavy chain IIA (NMMHCIIA), the predominant force-generating ATPase in non-muscle cells. Several lines of evidence implicate a role for MYH9 in podocytopathies. However, NMMHCIIA‘s function in podocytes remains unknown. To better understand this function, we performed immuno-precipitation followed by mass-spectrometry proteomics to identify proteins interacting with the NMMHCIIA-enriched actin-myosin complexes. Computational analyses revealed that these proteins belong to functional networks including regulators of cytoskeletal organization, metabolism and networks regulated by the HIV-1 gene nef. We further characterized the subcellular localization of NMMHCIIA within podocytes in vivo, and found it to be present within the podocyte major foot processes. Finally, we tested the effect of loss of MYH9 expression in podocytes in vitro, and found that it was necessary for cytoskeletal organization. Our results provide the first survey of NMMHCIIA-enriched actin-myosin-interacting proteins within the podocyte, demonstrating the important role of NMMHCIIA in organizing the elaborate cytoskeleton structure of podocytes. Our characterization of NMMHCIIA’s functions goes beyond the podocyte, providing important insights into its general molecular role.

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Section: Discussionmentioning

confidence: 99%

Proteomics Analysis of the Non-Muscle Myosin Heavy Chain IIa-Enriched Actin-Myosin Complex Reveals Multiple Functions within the Podocyte

et al. 2014

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“…Some papers suggest STAT3 promotes podocyte differentiation. In contrast, increased STAT3 activity caused podocyte proliferation and dedifferentiation in FSGS and HIVAN 51–53 , kidney diseases strongly associated with APOL1 variants 33, 54 .…”

Section: Apol1-activated Signaling Pathwaysmentioning

confidence: 95%

The Cell Biology of APOL1

O’Toole

Bruggeman

Madhavan

et al. 2017

Seminars in Nephrology

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The association of variants in the APOL1 gene, which encodes apolipoprotein L1 (APOL1), with progressive non-diabetic kidney diseases in African Americans has prompted intense investigation into the function(s) of APOL1. APOL1 is an innate immune effector that protects humans from infection by some trypanosomal parasites. We review the data characterizing APOL1 trypanolytic function, which has been a basis for studies of APOL1 function in mammalian cells. Subsequently, we discuss the studies that use animal models, mammalian cell culture models, and kidney biopsy tissue to discover the mechanisms of variant APOL1-associated kidney diseases.

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“…The Src SH3 domain allows for a critical interaction with Nef. This leads to ras-c-raf-MAPk1, 2 activation as well as Stat3 activation which in turn leads to podocyte proliferation and dedifferentiation [41]. As mentioned before, the PxxP domain of Nef is critical in this signal cascade: replacement of wild-type Nef with nef that has a mutation in the PxxP region abolishes the Nef-induced podocyte proliferation.…”

Section: Hiv-viral Protein-induced Cell Signaling In Podocytesmentioning

confidence: 99%

“…Src acts upstream of both pathways since transfecting HIV-1 podocytes with a dominant negative form of Src inhibits activation of Stat3 as well as MAPk1, 2. The dominant negative Src also prevents HIV infection from inducing dedifferentiation and proliferation of podocytes [41]. The importance of these two signaling pathways in podocytes has been confirmed in vivo.…”

Section: Hiv-viral Protein-induced Cell Signaling In Podocytesmentioning

confidence: 99%

“…Biopsies from patients with HIVAN were shown to have increased staining for phosphorylated Stat3 and MAPK1, 2. This was in contrast to a normal kidney biopsy as well as non-HIV kidney disease (FSGS) [41]. A mouse model expressing Nef selectively in podocytes also develops increased staining for phospho-Stat3 in podocytes in conjunction with early markers of proliferation and dedifferentiation [31].…”

Section: Hiv-viral Protein-induced Cell Signaling In Podocytesmentioning

confidence: 99%

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Podocytes in HIV-Associated Nephropathy

Klotman³

2007

Nephron Clin Pract

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HIV-associated nephropathy (HIVAN) is the leading cause of end-stage renal failure in HIV-1 seropositive patients. The pathologic findings include collapsing focal segmental glomerulosclerosis with proliferation of epithelial cells in Bowman’s space. Anatomically, these cells correspond to podocytes and exhibit a unique phenotype with loss of many differentiation markers including synaptopodin and dysregulation of the cell cycle markers consistent with proliferation. Podocyte dysfunction appears to be a direct result of HIV-1 protein expression, specifically Nef and Vpr as well as specific host factors that have yet to be elucidated. The mechanism by which Nef induces podocyte proliferation and dedifferentiation has been traced to its ability to activate several signaling pathways including Src-Stat3 and ras-raf-MAPK1, 2. Activation of the cAMP/PKA pathway with all-trans-retinoic acid appears to modulate these changes and returns podocytes to a differentiated, nonproliferating phenotype.

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Nef stimulates proliferation of glomerular podocytes through activation of Src-dependent Stat3 and MAPK1,2 pathways

Abstract: In collapsing focal segmental glomerulosclerosis (FSGS) of HIV-associated nephropathy (HIVAN),

Cited by 143 publications

References 48 publications

Proteomics Analysis of the Non-Muscle Myosin Heavy Chain IIa-Enriched Actin-Myosin Complex Reveals Multiple Functions within the Podocyte

Proteomics Analysis of the Non-Muscle Myosin Heavy Chain IIa-Enriched Actin-Myosin Complex Reveals Multiple Functions within the Podocyte

The Cell Biology of APOL1

Podocytes in HIV-Associated Nephropathy

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