TY - JOUR
T1 - Disease-associated polyalanine expansion mutations impair UBA6-dependent ubiquitination
AU - Amer-Sarsour, Fatima
AU - Falik, Daniel
AU - Berdichevsky, Yevgeny
AU - Kordonsky, Alina
AU - Eid, Sharbel
AU - Rabinski, Tatiana
AU - Ishtayeh, Hasan
AU - Cohen-Adiv, Stav
AU - Braverman, Itzhak
AU - Blumen, Sergiu C.
AU - Laviv, Tal
AU - Prag, Gali
AU - Vatine, Gad D.
AU - Ashkenazi, Avraham
N1 - Publisher Copyright:
© The Author(s) 2024.
PY - 2024/1/16
Y1 - 2024/1/16
N2 - Expansion mutations in polyalanine stretches are associated with a growing number of diseases sharing a high degree of genotypic and phenotypic commonality. These similarities prompted us to query the normal function of physiological polyalanine stretches and to investigate whether a common molecular mechanism is involved in these diseases. Here, we show that UBA6, an E1 ubiquitin-activating enzyme, recognizes a polyalanine stretch within its cognate E2 ubiquitin-conjugating enzyme USE1. Aberrations in this polyalanine stretch reduce ubiquitin transfer to USE1 and, subsequently, polyubiquitination and degradation of its target, the ubiquitin ligase E6AP. Furthermore, we identify competition for the UBA6-USE1 interaction by various proteins with polyalanine expansion mutations in the disease state. The deleterious interactions of expanded polyalanine tract proteins with UBA6 in mouse primary neurons alter the levels and ubiquitination-dependent degradation of E6AP, which in turn affects the levels of the synaptic protein Arc. These effects are also observed in induced pluripotent stem cell-derived autonomic neurons from patients with polyalanine expansion mutations, where UBA6 overexpression increases neuronal resilience to cell death. Our results suggest a shared mechanism for such mutations that may contribute to the congenital malformations seen in polyalanine tract diseases.
AB - Expansion mutations in polyalanine stretches are associated with a growing number of diseases sharing a high degree of genotypic and phenotypic commonality. These similarities prompted us to query the normal function of physiological polyalanine stretches and to investigate whether a common molecular mechanism is involved in these diseases. Here, we show that UBA6, an E1 ubiquitin-activating enzyme, recognizes a polyalanine stretch within its cognate E2 ubiquitin-conjugating enzyme USE1. Aberrations in this polyalanine stretch reduce ubiquitin transfer to USE1 and, subsequently, polyubiquitination and degradation of its target, the ubiquitin ligase E6AP. Furthermore, we identify competition for the UBA6-USE1 interaction by various proteins with polyalanine expansion mutations in the disease state. The deleterious interactions of expanded polyalanine tract proteins with UBA6 in mouse primary neurons alter the levels and ubiquitination-dependent degradation of E6AP, which in turn affects the levels of the synaptic protein Arc. These effects are also observed in induced pluripotent stem cell-derived autonomic neurons from patients with polyalanine expansion mutations, where UBA6 overexpression increases neuronal resilience to cell death. Our results suggest a shared mechanism for such mutations that may contribute to the congenital malformations seen in polyalanine tract diseases.
KW - Autonomic Nervous System
KW - Congenital Central Hypoventilation Syndrome
KW - Trinucleotide Repeats
KW - Ubiquitin Transfer System
KW - Ubiquitin-Activating Enzyme
UR - http://www.scopus.com/inward/record.url?scp=85182730248&partnerID=8YFLogxK
U2 - 10.1038/s44318-023-00018-9
DO - 10.1038/s44318-023-00018-9
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C2 - 38177505
AN - SCOPUS:85182730248
SN - 0261-4189
VL - 43
SP - 250
EP - 276
JO - EMBO Journal
JF - EMBO Journal
IS - 2
ER -