Numb family proteins play roles in Desmin and Vimentin localization at the Z-disc.

Desmin and Vimentin are major intermediate filaments at the Z-disc and play significant roles in sarcomere architecture and signaling transduction. Abnormal expression of sarcomeric Desmin and Vimentin (SDV) results in severe dysfunctions of striated muscles. In this study, it was found that paired Numb family proteins (NFPs), including Numb and its homolog Numblike, determined the range for the recruitment of SDV to the primitive Z-disc. Notably, NFPs were identified as SDV associated proteins and bound to the head, rod, and tail domains of SDV in a splicing-variant-dependent manner. Last, the construction and consolidation of the Z-disc was completed through the gradual adjustment of the position of SDV by clockwise/anticlockwise rotation of paired NFPs to 90° in the same direction. Conditional knockout of NFPs altered the arrangement and accumulated the expression level of SDV. This study further enriches the functions of NFPs in sarcomere assembly and maintenance through cooperation with SDV.