TY - JOUR
T1 - NEMO reshapes the α-Synuclein aggregate interface and acts as an autophagy adapter by co-condensation with p62
AU - Furthmann, Nikolas
AU - Bader, Verian
AU - Angersbach, Lena
AU - Blusch, Alina
AU - Goel, Simran
AU - Sánchez-Vicente, Ana
AU - Krause, Laura J.
AU - Chaban, Sarah A.
AU - Grover, Prerna
AU - Trinkaus, Victoria A.
AU - van Well, Eva M.
AU - Jaugstetter, Maximilian
AU - Tschulik, Kristina
AU - Damgaard, Rune Busk
AU - Saft, Carsten
AU - Ellrichmann, Gisa
AU - Gold, Ralf
AU - Koch, Arend
AU - Englert, Benjamin
AU - Westenberger, Ana
AU - Klein, Christine
AU - Jungbluth, Lisa
AU - Sachse, Carsten
AU - Behrends, Christian
AU - Glatzel, Markus
AU - Hartl, F. Ulrich
AU - Nakamura, Ken
AU - Christine, Chadwick W.
AU - Huang, Eric J.
AU - Tatzelt, Jörg
AU - Winklhofer, Konstanze F.
N1 - Publisher Copyright:
© 2023, The Author(s).
PY - 2023/12
Y1 - 2023/12
N2 - NEMO is a ubiquitin-binding protein which regulates canonical NF-κB pathway activation in innate immune signaling, cell death regulation and host-pathogen interactions. Here we identify an NF-κB-independent function of NEMO in proteostasis regulation by promoting autophagosomal clearance of protein aggregates. NEMO-deficient cells accumulate misfolded proteins upon proteotoxic stress and are vulnerable to proteostasis challenges. Moreover, a patient with a mutation in the NEMO-encoding IKBKG gene resulting in defective binding of NEMO to linear ubiquitin chains, developed a widespread mixed brain proteinopathy, including α-synuclein, tau and TDP-43 pathology. NEMO amplifies linear ubiquitylation at α-synuclein aggregates and promotes the local concentration of p62 into foci. In vitro, NEMO lowers the threshold concentrations required for ubiquitin-dependent phase transition of p62. In summary, NEMO reshapes the aggregate surface for efficient autophagosomal clearance by providing a mobile phase at the aggregate interphase favoring co-condensation with p62.
AB - NEMO is a ubiquitin-binding protein which regulates canonical NF-κB pathway activation in innate immune signaling, cell death regulation and host-pathogen interactions. Here we identify an NF-κB-independent function of NEMO in proteostasis regulation by promoting autophagosomal clearance of protein aggregates. NEMO-deficient cells accumulate misfolded proteins upon proteotoxic stress and are vulnerable to proteostasis challenges. Moreover, a patient with a mutation in the NEMO-encoding IKBKG gene resulting in defective binding of NEMO to linear ubiquitin chains, developed a widespread mixed brain proteinopathy, including α-synuclein, tau and TDP-43 pathology. NEMO amplifies linear ubiquitylation at α-synuclein aggregates and promotes the local concentration of p62 into foci. In vitro, NEMO lowers the threshold concentrations required for ubiquitin-dependent phase transition of p62. In summary, NEMO reshapes the aggregate surface for efficient autophagosomal clearance by providing a mobile phase at the aggregate interphase favoring co-condensation with p62.
UR - https://www.scopus.com/pages/publications/85179919134
U2 - 10.1038/s41467-023-44033-0
DO - 10.1038/s41467-023-44033-0
M3 - Article
C2 - 38114471
AN - SCOPUS:85179919134
SN - 2041-1723
VL - 14
JO - Nature communications
JF - Nature communications
IS - 1
M1 - 8368
ER -