USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder

Yi Heng Hao, Michael D. Fountain, Klementina Fon Tacer, Fan Xia, Weimin Bi, Sung Hae L Kang, Ankita Patel, Jill A. Rosenfeld, Cédric Le Caignec, Bertrand Isidor, Ian D. Krantz, Sarah E. Noon, Jean P. Pfotenhauer, Thomas M. Morgan, Rocio Moran, Robert C. Pedersen, Margarita S. Saenz, Christian P. Schaaf, Patrick Ryan Potts

Research output: Contribution to journalArticle

60 Citations (Scopus)

Abstract

Endosomal protein recycling is a fundamental cellular process important for cellular homeostasis, signaling, and fate determination that is implicated in several diseases. WASH is an actin-nucleating protein essential for this process, and its activity is controlled through K63-linked ubiquitination by the MAGE-L2-TRIM27 ubiquitin ligase. Here, we show that the USP7 deubiquitinating enzyme is an integral component of the MAGE-L2-TRIM27 ligase and is essential for WASH-mediated endosomal actin assembly and protein recycling. Mechanistically, USP7 acts as a molecular rheostat to precisely fine-tune endosomal F-actin levels by counteracting TRIM27 auto-ubiquitination/degradation and preventing overactivation of WASH through directly deubiquitinating it. Importantly, we identify de novo heterozygous loss-of-function mutations of USP7 in individuals with a neurodevelopmental disorder, featuring intellectual disability and autism spectrum disorder. These results provide unanticipated insights into endosomal trafficking, illuminate the cooperativity between an ubiquitin ligase and a deubiquitinating enzyme, and establish a role for USP7 in human neurodevelopmental disease. Hao et al. describe a function of the USP7 deubiquitinating enzyme in regulation of WASH/retromer-mediated endosomal protein recycling. USP7 functions as a molecular rheostat to prevent auto-ubiquitination and proteasomal degradation of TRIM27 E3 ubiquitin ligase, but also deubiquitinates WASH. Genetic studies identify cases of USP7 mutation/deletion resulting in a human neurodevelopmental disorder that overlaps with MAGE-L2 mutation.

Original languageEnglish (US)
Pages (from-to)956-969
Number of pages14
JournalMolecular Cell
Volume59
Issue number6
DOIs
StatePublished - Sep 17 2015

Fingerprint

Recycling
Ubiquitination
Ligases
Actins
Ubiquitin
Proteins
Mutation
Ubiquitin-Protein Ligases
Sequence Deletion
Intellectual Disability
Homeostasis
Neurodevelopmental Disorders
Deubiquitinating Enzymes

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

Cite this

USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder. / Hao, Yi Heng; Fountain, Michael D.; Fon Tacer, Klementina; Xia, Fan; Bi, Weimin; Kang, Sung Hae L; Patel, Ankita; Rosenfeld, Jill A.; Le Caignec, Cédric; Isidor, Bertrand; Krantz, Ian D.; Noon, Sarah E.; Pfotenhauer, Jean P.; Morgan, Thomas M.; Moran, Rocio; Pedersen, Robert C.; Saenz, Margarita S.; Schaaf, Christian P.; Potts, Patrick Ryan.

In: Molecular Cell, Vol. 59, No. 6, 17.09.2015, p. 956-969.

Research output: Contribution to journalArticle

Hao, YH, Fountain, MD, Fon Tacer, K, Xia, F, Bi, W, Kang, SHL, Patel, A, Rosenfeld, JA, Le Caignec, C, Isidor, B, Krantz, ID, Noon, SE, Pfotenhauer, JP, Morgan, TM, Moran, R, Pedersen, RC, Saenz, MS, Schaaf, CP & Potts, PR 2015, 'USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder', Molecular Cell, vol. 59, no. 6, pp. 956-969. https://doi.org/10.1016/j.molcel.2015.07.033
Hao, Yi Heng ; Fountain, Michael D. ; Fon Tacer, Klementina ; Xia, Fan ; Bi, Weimin ; Kang, Sung Hae L ; Patel, Ankita ; Rosenfeld, Jill A. ; Le Caignec, Cédric ; Isidor, Bertrand ; Krantz, Ian D. ; Noon, Sarah E. ; Pfotenhauer, Jean P. ; Morgan, Thomas M. ; Moran, Rocio ; Pedersen, Robert C. ; Saenz, Margarita S. ; Schaaf, Christian P. ; Potts, Patrick Ryan. / USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder. In: Molecular Cell. 2015 ; Vol. 59, No. 6. pp. 956-969.
@article{8ec747a514fa43fbb0c2bb8dc4d3c995,
title = "USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder",
abstract = "Endosomal protein recycling is a fundamental cellular process important for cellular homeostasis, signaling, and fate determination that is implicated in several diseases. WASH is an actin-nucleating protein essential for this process, and its activity is controlled through K63-linked ubiquitination by the MAGE-L2-TRIM27 ubiquitin ligase. Here, we show that the USP7 deubiquitinating enzyme is an integral component of the MAGE-L2-TRIM27 ligase and is essential for WASH-mediated endosomal actin assembly and protein recycling. Mechanistically, USP7 acts as a molecular rheostat to precisely fine-tune endosomal F-actin levels by counteracting TRIM27 auto-ubiquitination/degradation and preventing overactivation of WASH through directly deubiquitinating it. Importantly, we identify de novo heterozygous loss-of-function mutations of USP7 in individuals with a neurodevelopmental disorder, featuring intellectual disability and autism spectrum disorder. These results provide unanticipated insights into endosomal trafficking, illuminate the cooperativity between an ubiquitin ligase and a deubiquitinating enzyme, and establish a role for USP7 in human neurodevelopmental disease. Hao et al. describe a function of the USP7 deubiquitinating enzyme in regulation of WASH/retromer-mediated endosomal protein recycling. USP7 functions as a molecular rheostat to prevent auto-ubiquitination and proteasomal degradation of TRIM27 E3 ubiquitin ligase, but also deubiquitinates WASH. Genetic studies identify cases of USP7 mutation/deletion resulting in a human neurodevelopmental disorder that overlaps with MAGE-L2 mutation.",
author = "Hao, {Yi Heng} and Fountain, {Michael D.} and {Fon Tacer}, Klementina and Fan Xia and Weimin Bi and Kang, {Sung Hae L} and Ankita Patel and Rosenfeld, {Jill A.} and {Le Caignec}, C{\'e}dric and Bertrand Isidor and Krantz, {Ian D.} and Noon, {Sarah E.} and Pfotenhauer, {Jean P.} and Morgan, {Thomas M.} and Rocio Moran and Pedersen, {Robert C.} and Saenz, {Margarita S.} and Schaaf, {Christian P.} and Potts, {Patrick Ryan}",
year = "2015",
month = "9",
day = "17",
doi = "10.1016/j.molcel.2015.07.033",
language = "English (US)",
volume = "59",
pages = "956--969",
journal = "Molecular Cell",
issn = "1097-2765",
publisher = "Cell Press",
number = "6",

}

TY - JOUR

T1 - USP7 Acts as a Molecular Rheostat to Promote WASH-Dependent Endosomal Protein Recycling and Is Mutated in a Human Neurodevelopmental Disorder

AU - Hao, Yi Heng

AU - Fountain, Michael D.

AU - Fon Tacer, Klementina

AU - Xia, Fan

AU - Bi, Weimin

AU - Kang, Sung Hae L

AU - Patel, Ankita

AU - Rosenfeld, Jill A.

AU - Le Caignec, Cédric

AU - Isidor, Bertrand

AU - Krantz, Ian D.

AU - Noon, Sarah E.

AU - Pfotenhauer, Jean P.

AU - Morgan, Thomas M.

AU - Moran, Rocio

AU - Pedersen, Robert C.

AU - Saenz, Margarita S.

AU - Schaaf, Christian P.

AU - Potts, Patrick Ryan

PY - 2015/9/17

Y1 - 2015/9/17

N2 - Endosomal protein recycling is a fundamental cellular process important for cellular homeostasis, signaling, and fate determination that is implicated in several diseases. WASH is an actin-nucleating protein essential for this process, and its activity is controlled through K63-linked ubiquitination by the MAGE-L2-TRIM27 ubiquitin ligase. Here, we show that the USP7 deubiquitinating enzyme is an integral component of the MAGE-L2-TRIM27 ligase and is essential for WASH-mediated endosomal actin assembly and protein recycling. Mechanistically, USP7 acts as a molecular rheostat to precisely fine-tune endosomal F-actin levels by counteracting TRIM27 auto-ubiquitination/degradation and preventing overactivation of WASH through directly deubiquitinating it. Importantly, we identify de novo heterozygous loss-of-function mutations of USP7 in individuals with a neurodevelopmental disorder, featuring intellectual disability and autism spectrum disorder. These results provide unanticipated insights into endosomal trafficking, illuminate the cooperativity between an ubiquitin ligase and a deubiquitinating enzyme, and establish a role for USP7 in human neurodevelopmental disease. Hao et al. describe a function of the USP7 deubiquitinating enzyme in regulation of WASH/retromer-mediated endosomal protein recycling. USP7 functions as a molecular rheostat to prevent auto-ubiquitination and proteasomal degradation of TRIM27 E3 ubiquitin ligase, but also deubiquitinates WASH. Genetic studies identify cases of USP7 mutation/deletion resulting in a human neurodevelopmental disorder that overlaps with MAGE-L2 mutation.

AB - Endosomal protein recycling is a fundamental cellular process important for cellular homeostasis, signaling, and fate determination that is implicated in several diseases. WASH is an actin-nucleating protein essential for this process, and its activity is controlled through K63-linked ubiquitination by the MAGE-L2-TRIM27 ubiquitin ligase. Here, we show that the USP7 deubiquitinating enzyme is an integral component of the MAGE-L2-TRIM27 ligase and is essential for WASH-mediated endosomal actin assembly and protein recycling. Mechanistically, USP7 acts as a molecular rheostat to precisely fine-tune endosomal F-actin levels by counteracting TRIM27 auto-ubiquitination/degradation and preventing overactivation of WASH through directly deubiquitinating it. Importantly, we identify de novo heterozygous loss-of-function mutations of USP7 in individuals with a neurodevelopmental disorder, featuring intellectual disability and autism spectrum disorder. These results provide unanticipated insights into endosomal trafficking, illuminate the cooperativity between an ubiquitin ligase and a deubiquitinating enzyme, and establish a role for USP7 in human neurodevelopmental disease. Hao et al. describe a function of the USP7 deubiquitinating enzyme in regulation of WASH/retromer-mediated endosomal protein recycling. USP7 functions as a molecular rheostat to prevent auto-ubiquitination and proteasomal degradation of TRIM27 E3 ubiquitin ligase, but also deubiquitinates WASH. Genetic studies identify cases of USP7 mutation/deletion resulting in a human neurodevelopmental disorder that overlaps with MAGE-L2 mutation.

UR - http://www.scopus.com/inward/record.url?scp=84941811672&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84941811672&partnerID=8YFLogxK

U2 - 10.1016/j.molcel.2015.07.033

DO - 10.1016/j.molcel.2015.07.033

M3 - Article

C2 - 26365382

AN - SCOPUS:84941811672

VL - 59

SP - 956

EP - 969

JO - Molecular Cell

JF - Molecular Cell

SN - 1097-2765

IS - 6

ER -