Network approach to mutagenesis sheds insight on phage resistance in mycobacteria

Sinha, Saptarshi; Samaddar, Sourabh; Gupta, S. K.; Roy, Soumen

doi:10.1093/bioinformatics/btaa1103

Cited by 7 publications

(9 citation statements)

References 50 publications

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“…To understand the impact of GIV deletion, a similar network was prepared, except without GIV. The shortest path alteration fraction (Sinha et al , 2021 ) associated with Arf1 was calculated using differential shortest path analysis of the original and GIV‐depleted PPI network. Here only the paths having shortest path alteration fraction 1 were considered which indicated only the deleted or newly added shortest paths due to GIV deletion.…”

Section: Methodsmentioning

confidence: 99%

A circuit for secretion‐coupled cellular autonomy in multicellular eukaryotic cells

Qiao

Sinha

El-Hafeez

et al. 2023

Molecular Systems Biology

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Cancers represent complex autonomous systems, displaying self‐sufficiency in growth signaling. Autonomous growth is fueled by a cancer cell's ability to “secrete‐and‐sense” growth factors (GFs): a poorly understood phenomenon. Using an integrated computational and experimental approach, here we dissect the impact of a feedback‐coupled GTPase circuit within the secretory pathway that imparts secretion‐coupled autonomy. The circuit is assembled when the Ras‐superfamily monomeric GTPase Arf1, and the heterotrimeric GTPase Giαβγ and their corresponding GAPs and GEFs are coupled by GIV/Girdin, a protein that is known to fuel aggressive traits in diverse cancers. One forward and two key negative feedback loops within the circuit create closed‐loop control, allow the two GTPases to coregulate each other, and convert the expected switch‐like behavior of Arf1‐dependent secretion into an unexpected dose–response alignment behavior of sensing and secretion. Such behavior translates into cell survival that is self‐sustained by stimulus‐proportionate secretion. Proteomic studies and protein–protein interaction network analyses pinpoint GFs (e.g., the epidermal GF) as key stimuli for such self‐sustenance. Findings highlight how the enhanced coupling of two biological switches in cancer cells is critical for multiscale feedback control to achieve secretion‐coupled autonomy of growth factors.

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Section: Methodsmentioning

confidence: 99%

A circuit for secretion‐coupled cellular autonomy in multicellular eukaryotic cells

Qiao

Sinha

El-Hafeez

et al. 2023

Molecular Systems Biology

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“…The effect of perturbation on the protein-protein interaction network was calculated using node and edge-based centrality measurements. For each of the perturbations, changes in the centrality metrics were calculated using deference in the z score for rest of the nodes and edges to estimate the topological effect (Banerjee et al 2015; Sinha et al 2021) .…”

Section: Detailed Methodsmentioning

confidence: 99%

“…For each of the perturbations, changes in the centrality metrics were calculated using deference in the z score for rest of the nodes and edges to estimate the topological effect (Banerjee et al 2015;Sinha et al 2021).…”

Section: Protein-protein Interaction Network (Ppin) Construction and ...mentioning

confidence: 99%

Coupling of NOD2 to GIV is Required for Bacterial Sensing

Katkar

Anandachar

Sinha

et al. 2022

Preprint

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SUMMARYSensing of pathogens by Nucleotide oligomerization domain (NOD)-like 2 receptor (NOD2) induces a protective inflammatory response that coordinates bacterial clearance. Polymorphisms in NOD2 impair bacterial clearance, leading to chronic gut inflammation in Crohn’s disease (CD) via mechanisms that remain incompletely understood. We identify GIV/Girdin (CCDC88A) as a NOD2-interactor that shapes bacterial sensing-and-signaling in macrophages. Myeloid-specific GIV depletion exacerbated and protracted infectious colitis and abolished the protective effect of muramyl dipeptide (MDP) in both chemical colitis and severe sepsis. In the presence of GIV, macrophages enhance anti-bacterial pathways downstream of NOD2, clear microbes rapidly and concomitantly suppress inflammation. GIV’s actions are mediated via its C-terminus, which directly binds the terminal leucine-rich repeat (LRR#10) of NOD2; binding is augmented by MDP and ATP, precedes receptor oligomerization, and is abolished by the 1007fs CD-risk variant which lacks LRR#10. Findings illuminate mechanisms that underlie protective NOD2 signaling and loss of function in the major 1007fs variant.GRAPHIC ABSTRACTIn briefThis work reveals a mechanism by which macrophages use their innate immune sensor, NOD2, to protect the host against overzealous inflammation during bacterial infections, and the consequences of its loss, as occurs in the most important Crohn’s disease-risk variant.HIGHLIGHTSGIV is a functional and direct interactor of the terminal LRR repeat of NOD2Mice lacking MФ GIV develop dysbiosis, protracted ileocolitis and sepsisMDP/NOD2-dependent protective host responses require GIVCD-risk NOD2 1007fs variant lacking the terminal LRR#10 cannot bind GIV

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“…The list of proteins ( Dataset EV1 ) was used as ‘seed’ to generate the Golgi-specific Arf1-GIV network by fetching other connecting interactions and proteins from STRING database (Franceschini et al, 2013). The shortest path NetworkX algorithm (Sinha et al, 2021) was used to trace the connected proteins and interactions in between every possible pair of protein from the above-mentioned list. Highest possible interaction cutoff score was used to avoid false positive interactions.…”

Section: Methods and Protocolsmentioning

confidence: 99%

“…To understand the impact of GIV deletion, a similar network was prepared, except without GIV. Shortest path alteration fraction (Sinha et al, 2021) associated with Arf1 was calculated using differential shortest path analysis of the original and GIV-depleted PPI network. Here only the paths having shortest path alteration fraction 1, were considered which indicated only the deleted or newly added shortest paths due to GIV deletion.…”

Section: Methods and Protocolsmentioning

confidence: 99%

A Circuit for Secretion-coupled Cellular Autonomy in Multicellular Eukaryotes

Qiao

El-Hafeez

et al. 2021

Preprint

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SUMMARYIntercellular (between-cells) signals must be converted into an intracellular (within-cell) signal before it can trigger a proportionate response. How cells mount such proportionate responses within their interior remains unknown. Here we unravel the role of a coupled GTPase circuit on the Golgi membranes which enables the intracellular secretory machinery to respond proportionately to the growth factors in the extracellular space. The circuit, comprised of two species of biological switches, the Ras-superfamily monomeric GTPase Arf1, and the heterotrimeric GTPase, Giαβγ and their corresponding GAPs and GEFs, is coupled via at least one a forward and two key negative feedback loops. Interrogation of the circuit featuring such closed-loop control (CLC) using an integrated systems-based and experimental approach showed that CLC allows the two GTPases to mutually control each other and convert the expected switch-like behavior of Arf1 into an unexpected dose response aligned (DoRA) linear behavior. Such behavior translates into growth factor stimulated Giαβγ activity on Golgi membranes, temporal finiteness of Arf1 activity, and cellular secretion that is proportional to the stimuli. Findings reveal the importance of the coupled GTPase circuit in rendering concordant cellular responses via the faithful transmission of growth signals to the secretory machinery.GRAPHIC ABSTRACTHIGHLIGHTSEndo- (mono) and ectomembrane (trimeric) GTPase systems are believed to function independently.Their coupling in a closed loop system at the Golgi makes cell secretion proportionate to stimuli.Coupling enables closed-loop mutual control of both GTPases and dose response alignment (DoRA).Uncoupling creates an open loop which generates misaligned and discordant responses.

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Network approach to mutagenesis sheds insight on phage resistance in mycobacteria

Cited by 7 publications

References 50 publications

A circuit for secretion‐coupled cellular autonomy in multicellular eukaryotic cells

A circuit for secretion‐coupled cellular autonomy in multicellular eukaryotic cells

Coupling of NOD2 to GIV is Required for Bacterial Sensing

A Circuit for Secretion-coupled Cellular Autonomy in Multicellular Eukaryotes

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