Sustained Induction of Collagen Synthesis by TGF-β Requires Regulated Intramembrane Proteolysis of CREB3L1

CREB3L1 (cAMP response element binding protein 3-like 1), a transcription factor synthesized as a membrane-bound precursor and activated through Regulated Intramembrane Proteolysis (RIP), is essential for collagen production by osteoblasts during bone development. Here, we show that TGF-β (transforming growth factor-β), a cytokine known to stimulate production of collagen during wound healing and fibrotic diseases, induces proteolytic activation of CREB3L1 in human A549 cells. This activation results from inhibition of expression of TM4SF20 (transmembrane 4 L6 family member 20), which normally inhibits RIP of CREB3L1. Cleavage of CREB3L1 releases its NH2-terminal domain from membranes, allowing it to enter the nucleus where it binds to Smad4 to activate transcription of genes encoding proteins required for assembly of collagen-containing extracellular matrix. Our findings raise the possibility that inhibition of RIP of CREB3L1 could prevent excess deposition of collagen in certain fibrotic diseases.

CREB3L1（环腺苷酸应答元件结合蛋白3样蛋白1，cAMP response element binding protein 3-like 1）是一类以膜结合前体形式合成、经受调控膜内蛋白水解（Regulated Intramembrane Proteolysis，RIP）途径激活的转录因子，在骨骼发育过程中对成骨细胞合成胶原蛋白至关重要。本研究证实，转化生长因子-β（TGF-β，transforming growth factor-β）作为一种在伤口愈合与纤维化疾病中可刺激胶原蛋白生成的细胞因子，能够在人A549细胞中诱导CREB3L1的蛋白水解激活。该激活过程源于对TM4SF20（四次跨膜蛋白L6家族成员20，transmembrane 4 L6 family member 20）表达的抑制，而TM4SF20通常会抑制CREB3L1的受调控膜内蛋白水解过程。CREB3L1的裂解可将其氨基末端结构域从细胞膜上释放，使其能够进入细胞核并结合Smad4，从而激活编码胶原蛋白细胞外基质组装所需蛋白的基因的转录。本研究结果提示，抑制CREB3L1的受调控膜内蛋白水解过程，或可预防某些纤维化疾病中胶原蛋白的过度沉积。