Age-associated Decline in RAB-10 Efficacy Impairs Intestinal Barrier Integrity

Overview

Journal Nat Aging

Specialty Geriatrics

Date 2023 Aug 28

PMID 37640905

Authors

Jing Zhang

Zongyan Jiang

Changling Chen

Longfeng Yao

Ziwei Gao

Zihang Cheng

Yanling Yan

Hang Liu

Anbing Shi

Affiliations

Soon will be listed here.

Abstract

The age-related decline in the ability of the intestinal barrier to maintain selective permeability can lead to various physiological disturbances. Adherens junctions play a vital role in regulating intestinal permeability, and their proper assembly is contingent upon endocytic recycling. However, how aging affects the recycling efficiency and, consequently, the integrity of adherens junctions remains unclear. Here we show that RAB-10/Rab10 functionality is reduced during senescence, leading to impaired adherens junctions in the Caenorhabditis elegans intestine. Mechanistic analysis reveals that SDPN-1/PACSINs is upregulated in aging animals, suppressing RAB-10 activation by competing with DENN-4/GEF. Consistently, SDPN-1 knockdown alleviates age-related abnormalities in adherens junction integrity and intestinal barrier permeability. Of note, the inhibitory effect of SDPN-1 on RAB-10 requires KGB-1/JUN kinase, which presumably enhances the potency of SDPN-1 by altering its oligomerization state. Together, by examining age-associated changes in endocytic recycling, our study sheds light on how aging can impact intestinal barrier permeability.

Citing Articles

RAB-10 cooperates with EHBP-1 to capture vesicular carriers during post-Golgi exocytic trafficking.

Liu S, Wei J, Zhong L, Hai S, Song S, Xie C J Cell Biol. 2025; 224(4).

PMID: 39982707 PMC: 11844438. DOI: 10.1083/jcb.202410003.

Endosomal catabolism of phosphatidylinositol 4,5-bisphosphate is fundamental in building resilience against pathogens.

Yang C, Yao L, Chen D, Chen C, Li W, Tong H Protein Cell. 2024; 16(3):161-187.

PMID: 39087719 PMC: 11891140. DOI: 10.1093/procel/pwae041.

Apple polysaccharide improves age-matched cognitive impairment and intestinal aging through microbiota-gut-brain axis.

Zhang W, Zhong Y, Wang Z, Tang F, Zheng C Sci Rep. 2024; 14(1):16215.

PMID: 39003416 PMC: 11246462. DOI: 10.1038/s41598-024-67132-4.

References

Parrish A . The impact of aging on epithelial barriers. Tissue Barriers. 2017; 5(4):e1343172. PMC: 5788442. DOI: 10.1080/21688370.2017.1343172. View

Annese V, Latiano A, Palmieri O, Andriulli A . Dissecting genetic predisposition to inflammatory bowel disease: current progress and prospective application. Expert Rev Clin Immunol. 2010; 3(3):287-98. DOI: 10.1586/1744666X.3.3.287. View

Henckaerts L, Pierik M, Joossens M, Ferrante M, Rutgeerts P, Vermeire S . Mutations in pattern recognition receptor genes modulate seroreactivity to microbial antigens in patients with inflammatory bowel disease. Gut. 2007; 56(11):1536-42. PMC: 2095669. DOI: 10.1136/gut.2007.125468. View

Sandek A, Anker S, von Haehling S . The gut and intestinal bacteria in chronic heart failure. Curr Drug Metab. 2009; 10(1):22-8. DOI: 10.2174/138920009787048374. View

Walker J, Dieleman L, Mah D, Park K, Meddings J, Vethanayagam D . High prevalence of abnormal gastrointestinal permeability in moderate-severe asthma. Clin Invest Med. 2014; 37(2):E53-7. DOI: 10.25011/cim.v37i2.21086. View

Rera M, Clark R, Walker D . Intestinal barrier dysfunction links metabolic and inflammatory markers of aging to death in Drosophila. Proc Natl Acad Sci U S A. 2012; 109(52):21528-33. PMC: 3535647. DOI: 10.1073/pnas.1215849110. View

Egge N, Arneaud S, Wales P, Mihelakis M, McClendon J, Fonseca R . Age-Onset Phosphorylation of a Minor Actin Variant Promotes Intestinal Barrier Dysfunction. Dev Cell. 2019; 51(5):587-601.e7. PMC: 6897307. DOI: 10.1016/j.devcel.2019.11.001. View

Krug S, Schulzke J, Fromm M . Tight junction, selective permeability, and related diseases. Semin Cell Dev Biol. 2014; 36:166-76. DOI: 10.1016/j.semcdb.2014.09.002. View

Chen Y, Zhang J, Duan X . Changes of microvascular architecture, ultrastructure and permeability of rat jejunal villi at different ages. World J Gastroenterol. 2003; 9(4):795-9. PMC: 4611452. DOI: 10.3748/wjg.v9.i4.795. View

10.

Man A, Bertelli E, Rentini S, Regoli M, Briars G, Marini M . Age-associated modifications of intestinal permeability and innate immunity in human small intestine. Clin Sci (Lond). 2015; 129(7):515-27. DOI: 10.1042/CS20150046. View

11.

Shao X, Lucas B, Strauch J, Hardin J . The adhesion modulation domain of α-catenin regulates actin binding during morphogenesis. Mol Biol Cell. 2019; 30(17):2115-2123. PMC: 6743470. DOI: 10.1091/mbc.E19-01-0018. View

12.

Knust E, Bossinger O . Composition and formation of intercellular junctions in epithelial cells. Science. 2002; 298(5600):1955-9. DOI: 10.1126/science.1072161. View

13.

Cox E, Hardin J . Sticky worms: adhesion complexes in C. elegans. J Cell Sci. 2004; 117(Pt 10):1885-97. DOI: 10.1242/jcs.01176. View

14.

Kwiatkowski A, Maiden S, Pokutta S, Choi H, Benjamin J, Lynch A . In vitro and in vivo reconstitution of the cadherin-catenin-actin complex from Caenorhabditis elegans. Proc Natl Acad Sci U S A. 2010; 107(33):14591-6. PMC: 2930443. DOI: 10.1073/pnas.1007349107. View

15.

Muller H, Bossinger O . Molecular networks controlling epithelial cell polarity in development. Mech Dev. 2003; 120(11):1231-56. DOI: 10.1016/j.mod.2003.06.001. View

16.

Bernadskaya Y, Patel F, Hsu H, Soto M . Arp2/3 promotes junction formation and maintenance in the Caenorhabditis elegans intestine by regulating membrane association of apical proteins. Mol Biol Cell. 2011; 22(16):2886-99. PMC: 3154884. DOI: 10.1091/mbc.E10-10-0862. View

17.

Raich W, Agbunag C, Hardin J . Rapid epithelial-sheet sealing in the Caenorhabditis elegans embryo requires cadherin-dependent filopodial priming. Curr Biol. 1999; 9(20):1139-46. DOI: 10.1016/S0960-9822(00)80015-9. View

18.

Sumi A, Hayes P, DAngelo A, Colombelli J, Salbreux G, Dierkes K . Adherens Junction Length during Tissue Contraction Is Controlled by the Mechanosensitive Activity of Actomyosin and Junctional Recycling. Dev Cell. 2018; 47(4):453-463.e3. PMC: 6291457. DOI: 10.1016/j.devcel.2018.10.025. View

19.

Liu H, Wang S, Hang W, Gao J, Zhang W, Cheng Z . LET-413/Erbin acts as a RAB-5 effector to promote RAB-10 activation during endocytic recycling. J Cell Biol. 2017; 217(1):299-314. PMC: 5748983. DOI: 10.1083/jcb.201705136. View

20.

Gleason A, Nguyen K, Hall D, Grant B . Syndapin/SDPN-1 is required for endocytic recycling and endosomal actin association in the C. elegans intestine. Mol Biol Cell. 2016; . PMC: 5170557. DOI: 10.1091/mbc.E16-02-0116. View