Loss of MYO5B Leads to Reductions in Na+ Absorption With Maintenance of CFTR-Dependent Cl– Secretion in Enterocytes

Abstract

Although trafficking of many apical transporters is regulated by MYO5B, trafficking of CFTR is largely independent of MYO5B. Decreased apical localization of NHE3, SGLT1, DRA, and AQP7 might be responsible for dysfunctional water absorption in enterocytes of patients with MVID. Maintenance of apical CFTR might exacerbate water loss by active secretion of chloride into the intestinal lumen.

A V0-ATPase-dependent apical trafficking pathway maintains the polarity of the intestinal absorptive membrane

“…At the molecular level, a defective apical PM tethering of RAB-8 + /RAB-11 + endosomes by the molecular motor MYO5B (Knowles et al, 2014), which interacts with STX3 (Vogel et al, 2015) in concert with STXBP2, which has an accessory role in STX3-dependent vesicle tethering (Vogel et al, 2017b), has been proposed to be the major pathway leading to the MVID phenotype. Hence, MVID is strictly linked to a polarized trafficking defect and in vitro mammalian 2D or 3D cell culture models have been developed to study its currently ill-defined underlying mechanisms, based on MYO5B or Rab8/Rab11 silencing and disruption of MYO5B-Rab8/11 interactions (Feng et al, 2017;Knowles et al, 2014;Engevik et al, 2018;Kravtsov et al, 2016;Weis et al, 2016;Vogel et al, 2015;Schneeberger et al, 2015) as well as STX3 (Wiegerinck et al, 2014;Vogel et al, 2015) or STXBP2 (Mosa et al, 2018;Vogel et al, 2017b) mutations.…”

Loss of myosin Vb promotes apical bulk endocytosis in neonatal enterocytes

“…Alternatively, loss of Myo5b may alter trafficking patterns, leading to exaggeration of this pathway. The fragmentation of the giant lysosomes usually found in neonatal enterocytes suggests that processing of membranes into lysosomes may be impaired following Myo5b loss (Schneeberger et al, 2015;Weis et al, 2016;Engevik et al, 2018). Microvillus-lined inclusions in Myo5b KO mice were associated with membrane tubules containing the apical endosomal protein, endotubin, which is highly expressed in intestinal epithelium before weaning.…”

“…With loss of Myo5b, this pathway may be perturbed due to the blockade of trafficking that results from mutations in Myo5b. mice to generate Myo5b KO;LifeAct mice to visualize F-actin (Engevik et al, 2018). Mice heterozygous for Myo5b KO were crossed with Pacsin 2 KO mice to generate double KO mice that lack both Myo5b and Pacsin 2.…”

“…Mutations in the processive motor protein myosin Vb (Myo5b) are the primary drivers of MVID (Pohl et al, 1999;Erickson et al, 2008;Müller et al, 2008;Ruemmele et al, 2010;Szperl et al, 2011;Golachowska et al, 2012). Patients with MVID manifest enterocyte abnormalities, which includes subapical inclusions lined with discrete microvilli and decreased expression of apical nutrient transporters (Cutz et al, 1989;Ruemmele et al, 2006;Knowles et al, 2014;Engevik et al, 2018). To better understand the molecular mechanisms that underpin MVID, several laboratories, including our own, have created mouse models that recapitulate the major phenotypes of MVID patients (Cartón-García et al, 2015;Schneeberger et al, 2015;Weis et al, 2016;Engevik et al, 2018).…”

Exploiting Alternative Brush Border Trafficking Routes to Treat Microvillous Inclusion Disease

“…3 Biochemically, brush border expression of the Na þ -glucose cotransporter SGLT1 (Slc5a1), the N þ -H þ exchanger NHE3 (Slc9a3), and aquaporin 7 are markedly decreased in patients with MVID. 4 In contrast, brush border CFTR is maintained. 4 Given that NHE3 is a primary mediator of Na þ absorption, 5 that SGLT1 deficiency causes prominent diarrhea, 6 and that CFTR-mediated anion secretion drives voluminous diarrhea, 7 these abnormalities may explain the malabsorptive and secretory diarrhea that characterizes patients with MVID.…”