Sel1l, the human ortholog of the sel-1 gene of C. elegans, is a key component of the SEL1L-HRD1 protein complex, which represents the most conserved branch of endoplasmic reticulum-associated degradation (ERAD) [4]. ERAD plays critical roles in controlling protein homeostasis by degrading misfolded or terminally unfolded proteins, thus maintaining cellular function and integrity. Genetic models, such as KO/CKO mouse models, have been crucial in studying its functions.

In T cells, Sel1l deficiency leads to a reduced frequency and number of mature T cells, disrupts naïve CD8+ T-cell homeostasis, and fuels mTORC1/c-MYC activation and a metabolic shift due to enhanced IL-15 receptor expression. Also, it causes excessive ER stress, particularly aberrant activation of the PERK-ATF4-CHOP-Bim pathway [1]. In macrophages, SEL1L-HRD1 deficiency amplifies STING signalling and immunity against viral infection and tumour growth as they ubiquitinate and target nascent STING protein for proteasomal degradation in the basal state [2]. Hepatocyte-specific deletion of Sel1L predisposes mice to diet/chemical-induced tumors as WNT5A, a tumor suppressor, is misfolded and aggregated in the absence of SEL1L-HRD1 ERAD [3]. In mice with hepatocyte-specific Sel1L deficiency, basal iron homeostasis is altered, and they are sensitized to iron deficiency while resistant to iron overload as CP, a key ferroxidase, is a substrate of SEL1L-HRD1 ERAD [5]. T-cell-specific Sel1L deletion exacerbates experimental autoimmune encephalomyelitis (EAE) by promoting Th1/Th17-cell differentiation [6].

In conclusion, Sel1l, through its role in the SEL1L-HRD1 ERAD complex, is essential for maintaining protein homeostasis. Model-based research, especially KO/CKO mouse models, has revealed its significance in various biological processes and disease conditions, including T-cell survival and homeostasis, innate immunity, hepatocyte proliferation, systemic iron homeostasis, and the development of EAE. These findings enhance our understanding of the underlying mechanisms of these processes and potentially offer new therapeutic targets for related diseases.