Pleiotropy of C1QL proteins across physiological systems and their emerging role in synapse homeostasis.

The C1q/TNF superfamily of proteins engages in a pleiotropy of physiological functions associated with various diseases. C1QL proteins demonstrate important protective and regulatory roles in the endocrine, immune, cardiovascular, and nervous systems in both human and rodent studies. Studies in the central nervous system (CNS), adipose, and muscle tissue reveal several C1QL protein and receptor pathways altering multiple cellular responses, including cell fusion, morphology, and adhesion. This review examines C1QL proteins across these systems, summarizing functional and disease associations and highlighting cellular responses based on in vitro and in vivo data, receptor interaction partners, and C1QL-associated protein signaling pathways. We highlight the functions of C1QL proteins in organizing CNS synapses, regulating synapse homeostasis, maintaining excitatory synapses, and mediating signaling and trans-synaptic connections. Yet, while these associations are known, present studies provide insufficient insight into the underlying molecular mechanism of their pleiotropy, including specific protein interactions and functional pathways. Thus, we suggest several areas for more in-depth and interdisciplinary hypothesis testing.

C1QL3 promotes cell-cell adhesion by mediating complex formation between ADGRB3/BAI3 and neuronal pentraxins.

Synapses are the fundamental structural unit by which neurons communicate. An orchestra of proteins regulates diverse synaptic functions, including synapse formation, maintenance, and elimination-synapse homeostasis. Some proteins of the larger C1q super-family are synaptic organizers involved in crucial neuronal processes in various brain regions. C1Q-like (C1QL) proteins bind to the adhesion G protein-coupled receptor B3 (ADGRB3) and act at synapses in a subset of circuits. To investigate the hypothesis that the secreted C1QL proteins mediate tripartite trans-synaptic adhesion complexes, we conducted an in vivo interactome study and identified new binding candidates. We demonstrate that C1QL3 mediates a novel cell-cell adhesion complex involving ADGRB3 and two neuronal pentraxins, NPTX1 and NPTXR. Analysis of single-cell RNA-Seq data from the cerebral cortex shows that C1ql3, Nptx1, and Nptxr are highly co-expressed in the same excitatory neurons. Thus, our results suggest the possibility that in vivo the three co-expressed proteins are presynaptically secreted and form a complex capable of binding to postsynaptically localized ADGRB3, thereby creating a novel trans-synaptic adhesion complex. Identifying new binding partners for C1QL proteins and deciphering their underlying molecular principles will accelerate our understanding of their role in synapse organization.