Human Disease Model Report: fibrosis, pericellular accumulation of collagen IV

General Information

Name

fibrosis, pericellular accumulation of collagen IV

FlyBase ID

FBhh0001069

Disease Ontology Term

connective tissue disease

Parent Disease

OMIM

Overview

Basement membranes are polymers of extracellular matrix (ECM) proteins that underlie epithelia and surround organs in all animals; their main constituent is collagen IV. Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. This report describes a Drosophila model of fibrosis using fat body adipocytes, the main source of collagen IV in the larval stage. Using an adipocyte-specific driver, an extensive RNAi collection was screened for mislocalization of collagen IV (tracking one of the 2 genes that encode collagen IV alpha subunits in Drosophila, Col4a1 or vkg). Two genes from this screen that produce strong phenotypes of collagen IV accumulation at or near the plasma membrane were investigated further: Dmel\shi and Dmel\cact.

In the shi knockdown, accumulation of collagen IV occurs at the cell periphery, under a basement membrane surrounding the tissue. A dominant negative allele of shi produces a similar phenotype. Dmel\shi encodes dynamin; it is the highest-scoring ortholog of human DNM1, DNM2, and DNM3. shi is known to play a key role in endocytosis. Collagen IV accumulated in a shi-deficient adipocyte originates autonomously in that same cell. Experiments support the hypothesis that collagen is pericellularly accumulated in plasma membrane pockets that form as a consequence of failed endocytosis in shi-deficient adipocytes; other basement membrane components also accumulate in the plasma membrane pockets.

In the cact knockdown, pericellular accumulation of collagen IV in adipocytes is also observed. Since Dmel\cact encodes a negative regulator of the Toll signaling pathway, animals carrying a constitutively active mutation of Tl were also assessed; again, pericellular accumulation of collagen IV in adipocytes is observed. Plasma membrane overgrowth is observed, but appears to be due to increased secretory activity, rather than to reduced endocytosis.

In these cases, the abnormal accumulation of basement membrane components in fibrotic aggregates triggers an innate immune response, resulting in fat body melanization.

[updated Jul. 2019 by FlyBase; FBrf0222196]

Disease Summary Information

Disease Summary: fibrosis, pericellular accumulation of collagen IV

OMIM report

Human gene(s) implicated

Symptoms and phenotype

Fibrosis is defined by the overgrowth, hardening, and/or scarring of various tissues and is attributed to excess deposition of extracellular matrix components including collagen. Fibrosis is the end result of chronic inflammatory reactions induced by a variety of stimuli including persistent infections, autoimmune reactions, allergic responses, chemical insults, radiation, and tissue injury. Chronic inflammation and repair can trigger an excessive accumulation of extracellular matrix (ECM) components, which leads to the formation of a permanent fibrotic scar (Wynn, 2008; pubmed:18161745).

(FlyBase Curators, 2013-)

Genetics

Cellular phenotype and pathology

In mammals, the key cellular mediator of fibrosis is the myofibroblast, which when activated serves as the primary collagen-producing cell (Wynn, 2008; pubmed:18161745).

(FlyBase Curators, 2013-)

Molecular information

Basement membranes are polymers of extracellular matrix (ECM) proteins that underlie epithelia and surround organs in all animals. Their main constituent is collagen IV, a helical trimer consisting of three alpha chains, capable of forming polymeric networks that interact with other ECM proteins (FBrf0228918 and references cited therein).

(FlyBase Curators, 2013-)

External links

Disease synonyms

Related Diseases

Related human health report(s)

type IV collagenopathies

Ortholog Information

Human gene(s) in FlyBase

Other mammalian ortholog(s) used

D. melanogaster Gene Information (3)

Dmel\shi

Gene Snapshot

Contributions welcome

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

DLGTP

Comments on ortholog(s)

High-scoring ortholog of human DNM1, DNM2, and DNM3 (1 Drosophila to 3 human); multiple other homologous genes in both species. Dmel\shi shares 62-66% identity and 73-78% similarity with the human genes.

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Dmel\cact

Gene Snapshot

cactus (cact) encodes the homolog of mammalian IkappaB. cact product acts as an inhibitor of NF-kappaB signaling by binding to the products of dl and Dif, which prevents their nuclear translocation. Toll signaling promotes the destruction of cact protein, which allows the products of dl and Dif to enter the nucleus and regulate gene expression. [Date last reviewed: 2019-03-21]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

TL-NFN
IKB

Comments on ortholog(s)

Moderate-scoring ortholog of human NFKBIA; lower-scoring ortholog of multiple other genes in human. Dmel\cact shares 35% identity and 49% similarity with the human NFKBIA gene.

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Dmel\Tl

Gene Snapshot

Toll (Tl) encodes a transmembrane receptor that activates the Tl intracellular signaling pathway upon binding the ligand encoded by spz. It is involved in dorso-ventral embryonic patterning and immunity. [Date last reviewed: 2019-03-14]

Molecular function (GO)

Cellular component (GO)

Gene Groups / Pathways

Comments on ortholog(s)

Low-scoring ortholog of multiple toll-like receptors in human.

Orthologs and Alignments from DRSC

DIOPT - DRSC Integrative Ortholog Prediction Tool - Click the link below to search for orthologs in Humans

H. sapiens (Human)

Other Genes Used: Viral, Bacterial, Synthetic (0)

Summary of Physical Interactions (42 groups)

shi

protein-protein

Interacting group

Assay

References

shi - Cbl

anti bait coimmunoprecipitation, western blot

(Robertson et al., 2000)

shi - Cip4

anti tag coimmunoprecipitation, anti tag western blot

(Leibfried et al., 2008)

shi - Dap160

anti bait coimmunoprecipitation, western blot, pull down, far western blotting, edman degradation, autoradiography, cosedimentation, molecular weight estimation by staining

(Winther et al., 2015, Chen et al., 2014, Winther et al., 2013, Rodal et al., 2008, Kelly and Phillips, 2005, Verstreken et al., 2003, Razzaq et al., 2001, Robertson et al., 2000, Roos and Kelly, 1998)

shi - drk

anti tag coimmunoprecipitation, peptide massfingerprinting, pull down, autoradiography

(Friedman et al., 2011, Robertson et al., 2000)

shi - EndoA

anti bait coimmunoprecipitation, western blot, pull down

(Bademosi et al., 2023, Chen et al., 2014)

shi - Eps-15

anti bait coimmunoprecipitation, western blot

(Koh et al., 2007, Majumdar et al., 2006)

shi - ft

anti tag coimmunoprecipitation, peptide massfingerprinting

(Kwon et al., 2013)

shi - nwk

anti bait coimmunoprecipitation, western blot, pull down, two hybrid

(O'Connor-Giles et al., 2008, Rodal et al., 2008)

shi - p38a

anti tag coimmunoprecipitation, peptide massfingerprinting

(Belozerov et al., 2012)

shi - p38c

anti tag coimmunoprecipitation, peptide massfingerprinting

(Belozerov et al., 2012)

shi - sau

pull down, Identification by mass spectrometry, western blot

(Sechi et al., 2021)

shi - stnB

cosedimentation, western blot

(Kelly and Phillips, 2005)

shi - Synd

pull down, western blot

(Kumar et al., 2009)

shi - Syt1

cosedimentation, western blot

(Kelly and Phillips, 2005)

cact

protein-protein

Interacting group

Assay

References

cact

anti tag coimmunoprecipitation, western blot, two hybrid

(Fontenele et al., 2013, Edwards et al., 1997)

cact - CalpA

anti tag coimmunoprecipitation, anti tag western blot

(Fontenele et al., 2013)

cact - Dif

surface plasmon resonance, pull down, anti tag western blot, autoradiography, two hybrid

(Bitra et al., 2012, Minakhina et al., 2003, Lehming et al., 1995, Tatei and Levine, 1995)

cact - dl

protein cross-linking with a bifunctional reagent, western blot, pull down, autoradiography, anti bait coimmunoprecipitation, electrophoretic mobility shift assay, two hybrid, one hybrid, anti tag coimmunoprecipitation, anti tag western blot, surface plasmon resonance

(Palmer et al., 2019, Fontenele et al., 2013, Bitra et al., 2012, Minakhina et al., 2003, Bhaskar et al., 2000, Uv et al., 2000, Edwards et al., 1997, Yang and Steward, 1997, Govind et al., 1996, Lehming et al., 1995, Tatei and Levine, 1995, Isoda and Nusslein-Volhard, 1994, Whalen and Steward, 1993, Geisler et al., 1992, Kidd, 1992)

cact - Gprk2

anti tag coimmunoprecipitation, anti tag western blot

(Valanne et al., 2010)

cact - krz

anti tag coimmunoprecipitation, western blot, anti tag western blot

(Tipping et al., 2010)

cact - lwr

pull down, autoradiography

(Bhaskar et al., 2000)

cact - pll

enzymatic study, autoradiography

(Daigneault et al., 2013)

cact - Rel

two hybrid, surface plasmon resonance, pull down, anti tag western blot

(Bitra et al., 2012, Minakhina et al., 2003)

cact - SA1

anti tag coimmunoprecipitation, peptide massfingerprinting, experimental knowledge based

(Rhee et al., 2014)

cact - tub

anti bait coimmunoprecipitation, western blot

(Edwards et al., 1997)

protein-protein

Interacting group

Assay

References

comigration in non denaturing gel electrophoresis, disulfide bond, anti tag western blot, molecular sieving, enzyme linked immunosorbent assay, anti tag coimmunoprecipitation, pull down, autoradiography, electron microscopy, predetermined participant, cosedimentation in solution

(Ozkan et al., 2013, Gangloff et al., 2008, Weber et al., 2005, Hu et al., 2004, Luo et al., 2001)

Tl - Hrs

anti tag coimmunoprecipitation, anti tag western blot

(Huang et al., 2010)

Tl - Myd88

anti bait coimmunoprecipitation, anti tag western blot, anti tag coimmunoprecipitation

(Sun et al., 2004, Tauszig-Delamasure et al., 2002, Horng and Medzhitov, 2001)

Tl - Nmt

affinity chromatography technology, partial identification of protein sequence

(Ntwasa et al., 1997)

Tl - NT1

anti tag coimmunoprecipitation, anti tag western blot

(Chowdhury et al., 2019)

Tl - pll

pull down, autoradiography

(Luo et al., 2001)

Tl - spz

surface plasmon resonance, predetermined participant, x-ray crystallography, molecular sieving, electron microscopy, protein cross-linking with a bifunctional reagent, molecular weight estimation by staining, anti tag coimmunoprecipitation, anti tag western blot, pull down, autoradiography, inferred by author, isothermal titration calorimetry, cosedimentation, Identification by mass spectrometry, cosedimentation in solution

(Chowdhury et al., 2019, Parthier et al., 2014, Lewis et al., 2013, Stelter et al., 2013, Arnot et al., 2010, Gangloff et al., 2008, Weber et al., 2005, Hu et al., 2004, Weber et al., 2003)

Tl - spz5

anti tag coimmunoprecipitation, anti tag western blot

(Chowdhury et al., 2019)

Tl - Tehao

pull down, autoradiography

(Luo et al., 2001)

Tl - tub

anti bait coimmunoprecipitation, anti tag western blot

(Sun et al., 2004)

Tl - wek

anti tag coimmunoprecipitation, anti tag western blot

(Chen et al., 2006)

RNA-protein

Interacting group

Assay

References

Tl - Dcr-2

electrophoretic mobility shift assay, anti bait coimmunoprecipitation, quantitative reverse transcription pcr, anti tag coimmunoprecipitation, autoradiography, coimmunoprecipitation, affinity chromatography technology, western blot, northern blot, Identification by mass spectrometry, primer specific pcr

(Nadimpalli et al., 2022, Coll et al., 2018, Wang et al., 2015)

Tl - wisp

affinity chromatography technology, western blot, anti bait coimmunoprecipitation, quantitative reverse transcription pcr, Identification by mass spectrometry, primer specific pcr

(Coll et al., 2018, Cui et al., 2013)

RNA-RNA

Interacting group

Assay

References

Tl - mir-8

quantitative reverse transcription pcr, luminiscence technology

(Lee and Hyun, 2014)

Tl - mir-210

luminiscence technology

(Zhou et al., 2024)

Tl - mir-958

luminiscence technology, necessary binding region, western blot

(Li et al., 2017)

Tl - mir-962

quantitative reverse transcription pcr, luminiscence technology

(Li et al., 2021)

Alleles Reported to Model Human Disease (Disease Ontology) (21 alleles)

shi

Models Based on Experimental Evidence ( 2 )

Allele

Disease

Evidence

References

shi^JF03133

model of collagen disease

CEA

(Zang et al., 2015)

shi^UAS.cGa

model of autism spectrum disorder

CEA with α-Spec^UAS.cGa

(Grice et al., 2015)

Modifiers Based on Experimental Evidence ( 7 )

Allele

Disease

Interaction

References

shi^{ts1.IVS.p10.20xUAS}

ameliorates epilepsy

modeled by eas²

(Kroll et al., 2015)

modeled by para^bss1

(Kroll et al., 2015)

shi¹

ameliorates epilepsy

modeled by jus^iso7.8

(Kroll et al., 2015)

modeled by eas²

(Kroll et al., 2015)

modeled by para^bss1

(Kroll et al., 2015)

exacerbates neuronal ceroid lipofuscinosis

modeled by cathD¹

(Kuronen et al., 2009)

ameliorates Huntington's disease

modeled by Hsap\HTT^{128Q.1-336.UAS}

(Al-Ramahi et al., 2018)

shi^1.UAS

ameliorates epilepsy

modeled by para^bss1

(Kroll et al., 2015)

ameliorates high grade glioma

modeled by Pi3K92E^{UAS.Tag:MYC,Tag:PM(hKRAS)}, btl::Egfr^λ.UAS

(Losada-Pérez et al., 2022)

ameliorates colorectal cancer

modeled by SH3PX1^d1

(Zhang et al., 2019)

ameliorates tauopathy

modeled by Hsap\MAPT^{QUAS.2N4R.Tag:FLAG.T2A-GFP}

(Bankapalli et al., 2024)

shi²

ameliorates epilepsy

modeled by jus^iso7.8

(Kroll et al., 2015)

shi^ts.UAS.cUa

ameliorates epilepsy

modeled by zyd¹

(Weiss et al., 2019)

shi^JF03133

model of collagen disease

is ameliorated by PH4αEFB^GD771

(Zang et al., 2015)

shi^UAS.cUa

ameliorates amyotrophic lateral sclerosis type 10

modeled by Hsap\TARDBP^G298S.UAS

(Coyne et al., 2017)

modeled by Hsap\TARDBP^UAS.Tag:MYC

(Coyne et al., 2017)

cact

Models Based on Experimental Evidence ( 1 )

Allele

Disease

Evidence

References

cact^GL00627

model of collagen disease

CEA

(Zang et al., 2015)

Modifiers Based on Experimental Evidence ( 6 )

Allele

Disease

Interaction

References

cact^HM04020

ameliorates carcinoma

modeled by scrib^HMJ21977, yki^{S111A.S168A.S250A.UAS.Tag:V5}

(Snigdha et al., 2021)

cact⁷

ameliorates nervous system disease

modeled by Atpα^CJ10

(Talsma et al., 2014)

cact^E10

ameliorates hematologic cancer

modeled by lwr^4-3, lwr⁵

(Paddibhatla et al., 2010)

cact^KG07677

exacerbates Huntington's disease

modeled by Hsap\HTT^{128Q.1-336.UAS}

(Al-Ramahi et al., 2018)

cact^GL00627

model of collagen disease

is ameliorated by PH4αEFB^GD771

(Zang et al., 2015)

cact^KG00376

exacerbates Huntington's disease

modeled by Hsap\HTT^{128Q.1-336.UAS}

(Al-Ramahi et al., 2018)

Models Based on Experimental Evidence ( 4 )

Allele

Disease

Evidence

References

Tl^10b.UAS.cUa

model of glucose metabolism disease

CEA

(Roth et al., 2018)

Tl^rv1

model of primary immunodeficiency disease

CEA

(Zanette et al., 2013)

Tl^10b.UAS

model of collagen disease

CEA

(Zang et al., 2015)

Tl^r3

model of primary immunodeficiency disease

CEA

(Zanette et al., 2013)

Modifiers Based on Experimental Evidence ( 6 )

Allele

Disease

Interaction

References

Tl^10b.UAS.cUa

model of glucose metabolism disease

is ameliorated by Akt^{T342D.UAS.Tag:HA}

(Roth et al., 2018)

is ameliorated by Akt^{UAS.Tag:Myr(Unk)}

(Roth et al., 2018)

Tl^rv18

exacerbates tauopathy

modeled by Hsap\MAPT^UAS.cWa

(Feuillette et al., 2020)

Tl^rv1

ameliorates hematologic cancer

modeled by mxc^G46

(Remillieux-Leschelle et al., 2002)

Tl^10b.UAS

model of collagen disease

is ameliorated by PH4αEFB^GD771

(Zang et al., 2015)

ameliorates hematologic cancer

modeled by mxc¹

(Araki et al., 2019)

exacerbates carcinoma

modeled by scrib¹

(Katsukawa et al., 2018)

Tl^UASp.Venus

ameliorates cancer

modeled by dlg1^A40.2

(Parisi et al., 2014)

Tl^EP1051

exacerbates Alzheimer's disease

modeled by Hsap\APP^{Aβ42.GMR.Tag:SS(rPENK)}

(Cao et al., 2008)

exacerbates Huntington's disease

modeled by Hsap\HTT^Q93.ex1.UAS

(Cao et al., 2008)

Alleles Representing Disease-Implicated Variants

Genetic Tools, Stocks and Reagents

Sources of Stocks

Contact lab of origin for a reagent not available from a public stock center.

Bloomington Stock Center Disease Page

Related mammalian, viral, bacterial, or synthetic transgenes

Allele

Transgene

Publicly Available Stocks

Selected Drosophila transgenes

Allele

Transgene

Publicly Available Stocks

w^*; P{UAS-shi^ts1.K}3

shi^ts.UAS.cUa

P{UAS-shi.ts.U}

shi^{ts1.IVS.p10.20xUAS}

P{20XUAS-TTS-shi^ts1-p10}

y¹ w^*; PBac{20XUAS-IVS-shi^ts1-p10}VK00005

Tl^10b.UAS

P{UAS-Tl.10b}

P{UAS-Tl.10b}11, y¹ w^*

Tl^UASp.Venus

P{UASp-Tl.Venus}

w^*; P{UASp-Tl.Venus}4

Tl^10b.UAS.cUa

P{UAS-Tl.10b.U}

RNAi constructs available

Allele

Transgene

Publicly Available Stocks

shi^GD1529

P{GD1529}

w¹¹¹⁸; P{GD1529}v3798/TM3

y¹ v¹; P{TRiP.JF03133}attP2

shi^HMS00154

P{TRiP.HMS00154}

y¹ sc^* v¹ sev²¹; P{TRiP.HMS00154}attP2

y¹ v¹; P{TRiP.HM04020}attP2

cact^HMS00084

P{TRiP.HMS00084}

y¹ sc^* v¹ sev²¹; P{TRiP.HMS00084}attP2

cact^GL00627

P{TRiP.GL00627}

y¹ sc^* v¹ sev²¹; P{TRiP.GL00627}attP40

y¹ v¹; P{TRiP.JF01276}attP2

Tl^JF01491

P{TRiP.JF01491}

y¹ v¹; P{TRiP.JF01491}attP2

Tl^GL00474

P{TRiP.GL00474}

y¹ sc^* v¹ sev²¹; P{TRiP.GL00474}attP2

Selected Drosophila classical alleles

Allele

Allele class

Mutagen

Publicly Available Stocks

shi²

ethyl methanesulfonate

shi²

shi^12.12B

loss of function allele

X ray

shi²¹

loss of function allele

ethyl methanesulfonate

shi²¹/FM7c, P{GAL4-Kr.C}DC1, P{UAS-GFP.S65T}DC5, sn⁺

shi¹

ethyl methanesulfonate

shi¹; In(3LR)225/TM3, Sb¹

shi^FL54

loss of function allele

ethyl methanesulfonate

y¹ w^* shi^FL54 P{neoFRT}19A/FM7c

cact^E10

PM hybrid dysgenesis

cact^KG07677

P-element activity

y¹ w^67c23; P{SUPor-P}cact^KG07677

cact⁷

loss of function allele

ethyl methanesulfonate

Adc^b-1 cact⁷ pr¹/CyO

cact³

loss of function allele

ethyl methanesulfonate

cact^KG00376

y¹ w^67c23; P{SUPor-P}cact^KG00376/CyO

Tl^EP1051

P-element activity

Tl^rv22

loss of function allele

PM hybrid dysgenesis

Tl^rv12

loss of function allele

ethyl methanesulfonate

Tl^rv10

loss of function allele

ethyl methanesulfonate

Tl^r7

loss of function allele

ethyl methanesulfonate

Tl^rv1

loss of function allele

X ray

Tl^rv16

loss of function allele

ethyl methanesulfonate

Tl^rv18

loss of function allele

X ray

In(3LR)Tl^rv18, hry¹ Diap1^th-1 st¹ cu¹ Tl^rv18 ca¹/TM3, Sb¹

Tl^rv13

amorphic allele - genetic evidence

ethyl methanesulfonate

Tl^r3

ethyl methanesulfonate

Tl^r3 ca¹/TM3, Sb¹

Tl^r2

loss of function allele

ethyl methanesulfonate

Tl^rv9

loss of function allele

ethyl methanesulfonate

Tl^rv19

amorphic allele - genetic evidence

ethyl methanesulfonate

Tl^rv17

loss of function allele

ethyl methanesulfonate

Tl^rv15

loss of function allele

ethyl methanesulfonate

Tl^rv11

loss of function allele

ethyl methanesulfonate

Tl^rv4

amorphic allele - genetic evidence

X ray

Tl^r6

loss of function allele

ethyl methanesulfonate

Tl^rv24

amorphic allele - genetic evidence

Tl^reQ

amorphic allele - genetic evidence

Tl^rv25

amorphic allele - genetic evidence

Tl²

amorphic allele - genetic evidence

ethyl methanesulfonate

Tl^rv14

loss of function allele

ethyl methanesulfonate

Tl^rv23

loss of function allele

Tl^rv8

loss of function allele

ethyl methanesulfonate

Tl^rv21

loss of function allele

Tl^r4

loss of function allele

ethyl methanesulfonate

ru¹ hry¹ Diap1^th-1 st¹ kni^ri-1 rn^roe-1 p^p e¹ Tl^r4/TM3, Ser¹

Tl^rv7

loss of function allele

ethyl methanesulfonate

Tl^rv2

amorphic allele - genetic evidence

X ray

Tl^r1

loss of function allele

ethyl methanesulfonate

References (3)

Report Sections

Open Close