Sptlc2-flox Mouse

SPTLC2, serine palmitoyltransferase long chain base subunit 2, is a key subunit of serine palmitoyltransferase (SPT), the rate-limiting enzyme in de novo sphingolipid biosynthesis. Sphingolipids are important for cell membrane structure, cell-cell communication, and signaling pathways. SPTLC2 is thus crucial for normal cellular function and is involved in multiple biological processes [4,5,6,7].

In ALS, heterozygous SPTLC2 variants are associated with early-onset cases and frontotemporal dementia (FTD), with patients showing elevated plasma ceramide levels due to increased SPT activity and sphingolipid overproduction [1]. In ovarian cancer, depletion of SPTLC2 suppresses cell growth, migration, and metastasis, while overexpression promotes these processes through driving an EGFR-FAK-HBEGF signaling axis [2]. In osteoarthritis, overexpression of SPTLC2 in OA chondrocytes enhances cell viability, decreases apoptosis, and promotes ECM-related collagen expression while suppressing matrix metalloproteinase levels, and in vivo, it alleviates chondrocyte injuries [3]. In liver, ER stress upregulates SPTLC2, increasing ceramide levels and leading to reduced hepatic insulin response [4]. In CD8+ T cells, HSAN-I-associated SPTLC2 mutations dampen responses, and Sptlc2 deficiency in murine T cells impairs antiviral-T-cell expansion and effector function [5]. In tumors, a serine-free diet or Sptlc2 deficiency suppresses regulatory T cell accumulation and tumor growth [6].

In summary, SPTLC2 plays diverse and significant roles in various biological processes and disease conditions. Through functional studies, especially in relevant disease models, it is clear that SPTLC2-mediated sphingolipid metabolism is a key factor in neurodegenerative diseases like ALS, cancer development, and immune cell responses. Understanding SPTLC2 provides insights into disease mechanisms and potential therapeutic targets.