Multivalent lipid targeting by the calcium-independent C2A domain of synaptotagmin-like protein 4/granuphilin

Alnaas, Aml; Watson-Siriboe, Abena; Tran, Sherleen; Negussie, Mikias; Henderson, Jack A.; Osterberg, J. Ryan; Chon, Nara L.; Harrott, Beckston M.; Oviedo, Julianna; Lyakhova, Tatyana A.; Michel, Cole; Reisdorph, Nichole; Reisdorph, Richard; Shearn, Colin T.; Lin, Hai; Knight, Jefferson D.

doi:10.1074/jbc.ra120.014618

Cited by 11 publications

(28 citation statements)

References 70 publications

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“…Specifically, Rab27a and its effector Slp4 function in docking of MVBs on plasma membrane, and Rab27b and its effector Slac2b mediate the transfer of MVBs from the perinuclear area to the cell periphery [107]. Slp4 (also known as granuphilin) interacts with Rabs via its N-terminal Slp homology domain and binds to SNARE complex via a central linker region [108]. Park et al reported that disrupting the interaction between Rab27a and Slp4 with inhibitor BHMPS reduced exosome secretion and inhibited tumor growth of breast cancer cells [109].…”

Section: Rab Gtpasesmentioning

confidence: 99%

Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer

et al. 2022

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Exosomes are well-known key mediators of intercellular communication and contribute to various physiological and pathological processes. Their biogenesis involves four key steps, including cargo sorting, MVB formation and maturation, transport of MVBs, and MVB fusion with the plasma membrane. Each process is modulated through the competition or coordination of multiple mechanisms, whereby diverse repertoires of molecular cargos are sorted into distinct subpopulations of exosomes, resulting in the high heterogeneity of exosomes. Intriguingly, cancer cells exploit various strategies, such as aberrant gene expression, posttranslational modifications, and altered signaling pathways, to regulate the biogenesis, composition, and eventually functions of exosomes to promote cancer progression. Therefore, exosome biogenesis-targeted therapy is being actively explored. In this review, we systematically summarize recent progress in understanding the machinery of exosome biogenesis and how it is regulated in the context of cancer. In particular, we highlight pharmacological targeting of exosome biogenesis as a promising cancer therapeutic strategy.

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Section: Rab Gtpasesmentioning

confidence: 99%

Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer

et al. 2022

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“…There have been a number of MD studies of the interaction of Ca 2+ -dependent C2 domains with membranes, revealing how Ca 2+ ions mediate interactions between the protein and anionic lipids such as phosphatidylserine (PS) and phosphatidylinositol phosphates (PIPs) ( Alwarawrah and Wereszczynski, 2017 ; Banci et al., 2002 ; Chon et al., 2015 ; Jaud et al., 2007 ; Lai et al., 2010 ; Manna et al., 2008 ; Michaeli et al., 2017 ; Vermaas and Tajkhorshid, 2017 ). However, there have not been many simulation studies of the interactions of Ca 2+ -independent C2 domains with membranes (see, e.g., Alnaas et al., 2021 ; Scott et al., 2020 ) other than for PTEN ( Shenoy et al., 2012a ; Treece et al., 2020 ), despite the growing recognition of the importance of such interactions in a number of cellular processes ( Stahelin et al., 2014 ). Here, we use coarse-grained molecular dynamics (CG-MD) ( Ingólfsson et al., 2014 ; Marrink and Tieleman, 2013 ) to examine and compare the interactions of six different Ca 2+ -independent C2 domains with lipid bilayers: C2 domains from KIBRA (PDB: 6FJD ), PI3KC2α (PDB: 6BU0 ), RIM2 (PDB: 2BWQ ), PTEN (PDB: 1D5R ), Smurf2 (PDB: 2JQZ ), and SHIP2 (PDB: 5OKM ).…”

Section: Introductionmentioning

confidence: 99%

Binding of Ca2+-independent C2 domains to lipid membranes: A multi-scale molecular dynamics study

Larsen

Sansom

2021

Structure

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C2 domains facilitate protein interactions with lipid bilayers in either a Ca 2+ -dependent or -independent manner. We used molecular dynamics (MD) simulations to explore six Ca 2+ -independent C2 domains, from KIBRA, PI3KC2a, RIM2, PTEN, SHIP2, and Smurf2. In coarse-grained MD simulations these C2 domains formed transient interactions with zwitterionic bilayers, compared with longer-lived interactions with anionic bilayers containing phosphatidylinositol bisphosphate (PIP 2 ). Type I C2 domains bound non-canonically via the front, back, or side of the b sandwich, whereas type II C2 domains bound canonically, via the top loops. C2 domains interacted strongly with membranes containing PIP 2 , causing bound anionic lipids to cluster around the protein. Binding modes were refined via atomistic simulations. For PTEN and SHIP2, CG simulations of their phosphatase plus C2 domains with PIP 2 -containing bilayers were also performed, and the roles of the two domains in membrane localization compared. These studies establish a simulation protocol for membrane-recognition proteins.

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“… Twenty micrograms of recombinant p62 was treated with 4-HNE (molar ratio of 1:10) for 60 min, digested with trypsin, and analyzed using LC-MS/MS as previously described [ 28 , 44 ]. 4-HNE adducted residues are denoted in red (N = 3).…”

Section: Resultsmentioning

confidence: 99%

The autophagic protein p62 is a target of reactive aldehydes in human and murine cholestatic liver disease

et al. 2022

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Inflammatory cholestatic liver diseases, including Primary Sclerosing Cholangitis (PSC), are characterized by periportal inflammation with progression to cirrhosis. The objective of this study was to examine interactions between oxidative stress and autophagy in cholestasis. Using hepatic tissue from male acute cholestatic (bile duct ligated) as well as chronic cholestatic (Mdr2KO) mice, localization of oxidative stress, the antioxidant response and induction of autophagy were analyzed and compared to human PSC liver. Concurrently, the ability of reactive aldehydes to post-translationally modify the autophagosome marker p62 was assessed in PSC liver tissue and in cell culture. Expression of autophagy markers was upregulated in human and mouse cholestatic liver. Whereas mRNA expression of Atg12, Lamp1, Sqstm1 and Map1lc3 was increased in acute cholestasis in mice, it was either suppressed or not significantly changed in chronic cholestasis. In human and murine cholestasis, periportal hepatocytes showed increased IHC staining of ubiquitin, 4-HNE, p62, and selected antioxidant proteins. Increased p62 staining colocalized with accumulation of 4-HNE-modified proteins in periportal parenchymal cells as well as with periportal macrophages in both human and mouse liver. Mechanistically, p62 was identified as a direct target of lipid aldehyde adduction in PSC hepatic tissue and in vitro cell culture. In vitro LS-MS/MS analysis of 4-HNE treated recombinant p62 identified carbonylation of His123, Cys128, His174, His181, Lys238, Cys290, His340, Lys341 and His385. These data indicate that dysregulation of autophagy and oxidative stress/protein damage are present in the same periportal hepatocyte compartment of both human and murine cholestasis. Thus, our results suggest that both increased expression as well as ineffective autophagic degradation of oxidatively-modified proteins contributes to injury in periportal parenchymal cells and that direct modification of p62 by reactive aldehydes may contribute to autophagic dysfunction.

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Multivalent lipid targeting by the calcium-independent C2A domain of synaptotagmin-like protein 4/granuphilin

Cited by 11 publications

References 70 publications

Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer

Exosome biogenesis: machinery, regulation, and therapeutic implications in cancer

Binding of Ca2+-independent C2 domains to lipid membranes: A multi-scale molecular dynamics study

The autophagic protein p62 is a target of reactive aldehydes in human and murine cholestatic liver disease

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