E3 ubiquitin ligase RNF13 involves spatial learning and assembly of the SNARE complex.
Changes in the structure and number of synapses modulate learning, memory and cognitive disorders. Ubiquitin-mediated protein modification is a key mechanism for regulating synaptic activity, though the precise control of this process remains poorly understood. RING finger protein 13 (RNF13) is a recently identified E3 ubiquitin ligase, and its in vivo function remains completely unknown. We show here that genetic deletion of RNF13 in mice leads to a significant deficit in spatial learning as determined by the Morris water maze test and Y-maze learning test. At the ultrastructral level, the synaptic vesicle density was decreased and the area of the active zone was increased at hippocampal synapses of RNF13-null mice compared with those of wild-type littermates. We found no change in the levels of SNARE (soluble N-ethylmaleimide-sensitive factor-attachment protein receptor) complex proteins in the hippocampus of RNF13-null mice, but impaired SNARE complex assembly. RNF13 directly interacted with snapin, a SNAP-25-interacting protein. Interestingly, snapin was ubiquitinated by RNF13 via the lysine-29 conjugated polyubiquitin chain, which in turn promoted the association of snapin with SNAP-25. Consistently, we found an attenuated interaction between snapin and SNAP-25 in the RNF13-null mice. Therefore, these results suggest that RNF13 is involved in the regulation of the SNARE complex, which thereby controls synaptic function.
Key Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Tsinghua University, Beijing, 100005, China.
Qiang
Q
Zhang
Yanfeng
Y
Li
Lei
L
Zhang
Nan
N
Yang
Jiao
J
Meng
Pingping
P
Zuo
Yong
Y
Zhang
Jie
J
Chen
Li
L
Wang
Xiang
X
Gao
Dahai
D
Zhu
D000818:Animals; D006624:Hippocampus / Q000378:metabolism / Q000648:ultrastructure; D018782:Maze Learning / Q000502:physiology; D051379:Mice; D018345:Mice, Knockout; D050600:SNARE Proteins / Q000378:metabolism*; D013569:Synapses / Q000235:genetics / Q000648:ultrastructure; D013572:Synaptic Vesicles / Q000235:genetics / Q000648:ultrastructure; D050825:Synaptosomal-Associated Protein 25 / Q000378:metabolism / Q000502:physiology; D044767:Ubiquitin-Protein Ligases / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D054875:Ubiquitination; D033921:Vesicular Transport Proteins / Q000378:metabolism
D050600:SNARE Proteins; C494209:Snap25 protein, mouse; C498451:Snapin protein, mouse; D050825:Synaptosomal-Associated Protein 25; D033921:Vesicular Transport Proteins; C539844:RNF13 protein, mouse; D044767:Ubiquitin-Protein Ligases