Feng Qiang, Bonder Edward M, Engevik Amy C, Zhang Lanjing, Tyska Matthew J, Goldenring James R, Gao Nan
Department of Biological Sciences, Rutgers University, Newark, NJ 07102, USA.
Department of Surgery, and Epithelial Biology Center, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
J Cell Sci. 2017 Aug 1;130(15):2491-2505. doi: 10.1242/jcs.201897. Epub 2017 Jun 8.
Misplaced formation of microvilli to basolateral domains and intracellular inclusions in enterocytes are pathognomonic features in congenital enteropathy associated with mutation of the apical plasma membrane receptor syntaxin 3 (STX3). Although the demonstrated binding of Myo5b to the Rab8a and Rab11a small GTPases implicates cytoskeleton-dependent membrane sorting, the mechanisms underlying the microvillar location defect remain unclear. By selective or combinatory disruption of Rab8a and Rab11a membrane traffic , we demonstrate that transport of distinct cargo to the apical brush border rely on either individual or both Rab regulators, whereas certain basolateral cargos are redundantly transported by both factors. Enterocyte-specific and double-knockout mouse neonates showed immediate postnatal lethality and more severe enteropathy than single knockouts, with extensive formation of microvilli along basolateral surfaces. Notably, following an inducible deletion from neonatal enterocytes, basolateral microvilli were induced within 3 days. These data identify a potentially important and distinct mechanism for a characteristic microvillus defect exhibited by enterocytes of patients with neonatal enteropathy.
微绒毛错位形成于肠上皮细胞的基底外侧结构域以及细胞内包含物，是与顶端质膜受体 syntaxin 3（STX3）突变相关的先天性肠病的特征性表现。虽然已证实 Myo5b 与 Rab8a 和 Rab11a 小 GTP 酶结合涉及细胞骨架依赖性膜分选，但微绒毛定位缺陷的潜在机制仍不清楚。通过选择性或联合破坏 Rab8a 和 Rab11a 的膜运输，我们证明不同货物向顶端刷状缘的运输依赖于单个或两个 Rab 调节因子，而某些基底外侧货物则由这两个因子冗余运输。肠上皮细胞特异性和双敲除小鼠新生儿出生后立即死亡，且比单敲除小鼠患有更严重的肠病，其基底外侧表面有大量微绒毛形成。值得注意的是，在从新生肠上皮细胞中进行诱导性缺失后，3 天内即可诱导基底外侧微绒毛的形成。这些数据确定了一种潜在的重要且独特的机制，可解释新生儿肠病患者肠上皮细胞所表现出的特征性微绒毛缺陷。
