PMID- 34782467 OWN - NLM STAT- MEDLINE DCOM- 20211221 LR - 20220516 IS - 1091-6490 (Electronic) IS - 0027-8424 (Print) IS - 0027-8424 (Linking) VI - 118 IP - 47 DP - 2021 Nov 23 TI - The K63 deubiquitinase CYLD modulates autism-like behaviors and hippocampal plasticity by regulating autophagy and mTOR signaling. LID - 10.1073/pnas.2110755118 [doi] LID - e2110755118 AB - Nondegradative ubiquitin chains attached to specific targets via Lysine 63 (K63) residues have emerged to play a fundamental role in synaptic function. The K63-specific deubiquitinase CYLD has been widely studied in immune cells and lately also in neurons. To better understand if CYLD plays a role in brain and synapse homeostasis, we analyzed the behavioral profile of CYLD-deficient mice. We found that the loss of CYLD results in major autism-like phenotypes including impaired social communication, increased repetitive behavior, and cognitive dysfunction. Furthermore, the absence of CYLD leads to a reduction in hippocampal network excitability, long-term potentiation, and pyramidal neuron spine numbers. By providing evidence that CYLD can modulate mechanistic target of rapamycin (mTOR) signaling and autophagy at the synapse, we propose that synaptic K63-linked ubiquitination processes could be fundamental in understanding the pathomechanisms underlying autism spectrum disorder. FAU - Colombo, Elisa AU - Colombo E AD - Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. AD - Institute for Microscopic Anatomy and Neurobiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. AD - Focus Program Translational Neurosciences, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. FAU - Horta, Guilherme AU - Horta G AD - Institute for Microscopic Anatomy and Neurobiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. FAU - Roesler, Mona K AU - Roesler MK AUID- ORCID: 0000-0003-1276-7324 AD - Institute for Microscopic Anatomy and Neurobiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. FAU - Ihbe, Natascha AU - Ihbe N AUID- ORCID: 0000-0002-6514-2806 AD - Institute for Physiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. FAU - Chhabra, Stuti AU - Chhabra S AD - Institute for Microscopic Anatomy and Neurobiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. AD - Focus Program Translational Neurosciences, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. FAU - Radyushkin, Konstantin AU - Radyushkin K AD - Mouse Behavior Unit, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. FAU - Di Liberto, Giovanni AU - Di Liberto G AUID- ORCID: 0000-0001-6788-0215 AD - Division of Clinical Pathology, Department of Pathology and Immunology, Geneva University Hospitals CH-1211 Geneva, Switzerland. FAU - Kreutzfeldt, Mario AU - Kreutzfeldt M AUID- ORCID: 0000-0003-0335-2733 AD - Division of Clinical Pathology, Department of Pathology and Immunology, Geneva University Hospitals CH-1211 Geneva, Switzerland. FAU - Schumann, Sven AU - Schumann S AD - Institute for Microscopic Anatomy and Neurobiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. FAU - von Engelhardt, Jakob AU - von Engelhardt J AUID- ORCID: 0000-0003-3861-3294 AD - Focus Program Translational Neurosciences, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. AD - Institute for Pathophysiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. FAU - Merkler, Doron AU - Merkler D AD - Division of Clinical Pathology, Department of Pathology and Immunology, Geneva University Hospitals CH-1211 Geneva, Switzerland. FAU - Behl, Christian AU - Behl C AD - Focus Program Translational Neurosciences, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. AD - Institute for Pathobiochemistry, The Autophagy Lab, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. FAU - Mittmann, Thomas AU - Mittmann T AUID- ORCID: 0000-0001-6002-2963 AD - Focus Program Translational Neurosciences, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. AD - Institute for Physiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. FAU - Clement, Albrecht M AU - Clement AM AUID- ORCID: 0000-0002-6058-7507 AD - Focus Program Translational Neurosciences, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. AD - Institute for Pathobiochemistry, The Autophagy Lab, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. FAU - Waisman, Ari AU - Waisman A AUID- ORCID: 0000-0003-4304-8234 AD - Institute for Molecular Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany; waisman@uni-mainz.de mschmeisser@uni-mainz.de. AD - Focus Program Translational Neurosciences, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. AD - Research Center for Immunotherapy, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. FAU - Schmeisser, Michael J AU - Schmeisser MJ AUID- ORCID: 0000-0002-5514-1922 AD - Institute for Microscopic Anatomy and Neurobiology, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany; waisman@uni-mainz.de mschmeisser@uni-mainz.de. AD - Focus Program Translational Neurosciences, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz 55131, Germany. LA - eng PT - Journal Article PT - Research Support, Non-U.S. Gov't PT - Research Support, U.S. Gov't, Non-P.H.S. PL - United States TA - Proc Natl Acad Sci U S A JT - Proceedings of the National Academy of Sciences of the United States of America JID - 7505876 RN - 0 (Microfilament Proteins) RN - 0 (Nerve Tissue Proteins) RN - 0 (Shank3 protein, mouse) RN - 0 (Ubiquitin) RN - EC 2.7.1.1 (mTOR protein, mouse) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) RN - EC 3.4.19.12 (CYLD protein, mouse) RN - EC 3.4.19.12 (Deubiquitinating Enzyme CYLD) RN - K3Z4F929H6 (Lysine) SB - IM MH - Animals MH - Autism Spectrum Disorder MH - Autistic Disorder MH - Autophagy/*physiology MH - Deubiquitinating Enzyme CYLD MH - Female MH - Hippocampus/*metabolism MH - Lysine/metabolism MH - Male MH - Mice MH - Mice, Inbred C57BL MH - Microfilament Proteins MH - Nerve Tissue Proteins MH - Neurons/metabolism MH - Signal Transduction/*physiology MH - Synapses/metabolism MH - TOR Serine-Threonine Kinases/*metabolism MH - Ubiquitin/metabolism MH - Ubiquitination PMC - PMC8617491 OTO - NOTNLM OT - CYLD OT - autism spectrum disorder OT - autophagy OT - mTOR signaling OT - synapse COIS- The authors declare no competing interest. EDAT- 2021/11/17 06:00 MHDA- 2021/12/22 06:00 PMCR- 2022/05/15 CRDT- 2021/11/16 06:13 PHST- 2021/09/21 00:00 [accepted] PHST- 2021/11/16 06:13 [entrez] PHST- 2021/11/17 06:00 [pubmed] PHST- 2021/12/22 06:00 [medline] PHST- 2022/05/15 00:00 [pmc-release] AID - 2110755118 [pii] AID - 202110755 [pii] AID - 10.1073/pnas.2110755118 [doi] PST - ppublish SO - Proc Natl Acad Sci U S A. 2021 Nov 23;118(47):e2110755118. doi: 10.1073/pnas.2110755118.