**5. LUBAC-Related Disorders**

NF-κB signaling plays pivotal roles in the innate and adaptive immune responses, and anti-apoptosis. Therefore, the impaired NF-κB activation is closely associated with various disorders, such as cancers, inflammatory, autoimmune, and neurodegenerative diseases, and metabolic syndrome [33,130]. In this chapter, we introduce the disorders closely associated with the dysregulation of the linear ubiquitin code.

### *5.1. Genetic Deficiency of LUBAC Subunits and Related Diseases*

The *Hoip* [34] or *Hoil-1l* [131] knockout mice are embryonic lethal, while the spontaneous deficiency of *Sharpin* reportedly induces severe dermatitis [60], indicating that the LUBAC activity is crucial for development and homeostasis. In humans, inherited *HOIL-1L* mutations reportedly induce polyglucosan body myopathy with or without immunodeficiency and autoinflammation (Table 1) [132–134]. Moreover, the L72P missense mutation in the PUB domain of *HOIP* in a patient with multiorgan autoinflammation, immunodeficiency, amylopectinosis, and systemic lymphangiectasia [135], and another case of *HOIP* deficiency with early-onset immunodeficiency and autoinflammation, but not amylopectinosis and lymphangiectasia [136], were recently identified. These *HOIP* mutations a ffect the expression of type I IFN regulated genes. Taken together, these results indicate that the LUBAC activity is required to suppress myopathy, systemic inflammation, and immunodeficiency in humans.


**Table 1.** Genetic deficiencies of human *HOIL-1L* and *HOIP*, and their symptoms.
